Cleaning Validation Ppt Pharmaceutical validation

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CLEANING VALIDATION
Shree WaranaVibhagShikshan Mandal's
Tatyasaheb Kore College of Pharmacy, Warananagar
Created By
Miss. A. B. Patil
M. Pharm (Pharmaceutical Chemistry)
Assistant Professor

CLEANING VALIDATION
Validation: Validation is the documented evidence that a procedure
or activity will consistently give expected results.
Cleaning Validation: Cleaning validation is the documented
evidence that ensures the equipment and the part of equipment is
effectively cleaned and provides consistent results.
 It gives reliability that the equipment used for production are free
from older API, Cleaning materials, and other micro-organisms.
 The cleaning procedures are followed to prevent cross-
contamination and the adulteration. If cleaning not performed
adequately then the potential damage might cause to the product
quality and safety of the patients health.

CLEANING VALIDATION
Objectives:
 The objective of cleaning validation is to prevent the
contamination and adulteration of the present batch with
various residues, excipients, microbes, detergent agents, which
are used in previous batch.
 The cleaning validation of the areas where it is difficult to
reach and areas where there is no direct contact of the drug like
fans, flanges, shafts, heating elements are to be considered.

WHY IS CLEANING VALIDATION REQUIRED?
 Need by regulatory authorities so control and quality can be
maintained.
 Conformity of safety and purity of the product.
 Assurance to consumers that product is safe and quality is built
into it.
 Cleaning validation ensures process quality and builds internal
control

ADVANTAGE OF CLEANING VALIDATION
 Assurance of quality & safety.
 Government regulations.
 Product integrity,
 Microbial integrity,
 Cross contamination integrity,
 Batch integrity,
 Equipment reuse,
 Reduction of quality costs.
 Making good business sense.
 Less down time, fewer batch failures and may operate / clean more
efficiently.

TYPES OF CONTAMINATION
1. Cross contamination:
 Contamination which can be caused by residues of the
previous batch interacting with present batch.
 This interaction cannot be tolerated because this can cause
high adverse effects to the consumers.
 It may also cause synergetic effects when interacted with
other drugs causing various pharmacological actions.

2. Contaminated by unintended materials:
 The various unintended materials like equipment parts,
lubricants, chemical agents, cloth fibers, brushes etc…used
for cleaning may interact with drug causing unwanted
interaction.
3. Microbial contamination:
 Microbes may get evolve due to presence of residues either
by storage or during the process

2. Contaminated by unintended materials:
 The various unintended materials like equipment parts,
lubricants, chemical agents, cloth fibers, brushes etc…used
for cleaning may interact with drug causing unwanted
interaction.
3. Microbial contamination:
 Microbes may get evolve due to presence of residues either
by storage or during the process.

CLEANING METHOD DEVELOPMENT
 Cleaning method development is a systematic process to create
and validate effective cleaning procedures in pharmaceutical
industries , where product purity and safety are paramount.
 This involves understanding the nature of residues, selecting
appropriate cleaning agents and methods, and validating the
procedure to ensure consistent and complete removal of
contaminants.

REQUIREMENTS OF FDA
 A SOP should be present for each cleaning process for different
equipment.
 If the companies prefer a specific cleaning procedure for each
batch of same product produced, a separate SOP should be written
cleaning procedure.
 A SOP should be written for different cleaning procedure for
product changes by the firms.
 If firms follow separate procedures for cleaning the water soluble
residues and non water soluble residues FDA expects a written
procedure for each process.

REQUIREMENTS OF FDA
 A written document is required for each validation procedure
performed in specific equipment.
 Personnel performing validation should check with procedures,
limits and acceptance criteria before reporting and approving.
 The firms should follow the protocols and document the results of
the studies.
 The regulatory authorities are the end bodies to approve the final
reports which confirms cleaning is effective and product safety

CLEANING PROCEDURES
 Standard cleaning procedures
for all equipment and parts of
equipment should be prepared.
 Complete evaluation should be
done from the equipment,
residues, use of washing
solvents, and cleaning
techniques. Cleaning
procedures should remove all
the potential threats.
Parameters of equipment to be
considered

CLEANING PROCEDURES
Levels Attributes Cleaning
validation
Level 1 Batch to batch
cleaning in an identical
process
Not required
Level 2 Change over between
intermediate of one
product to final
intermediate of another
product
Required but not
necessary
Level 3 Change over from one
API to another API
Essential

CLEANING AGENT
 Cleaning agent used, scientifically
justified and based on different aspects.
 The solubility of the materials to be
removed should be considered.
 The design and construction of the
equipment and surface materials to be
cleaned should be studied.
 The degree of safety of the cleaning
agent should be known.
 The detection feasibility and ease of
removal should be possible.
Criteria for cleaning agents to
be used

CLEANING AGENT
 There are a variety of cleaning agent options available to
pharmaceutical companies for their cleaning processes.
 it may be a combination of detergent and water or other agent like
chelating agents.
 The properties of cleaning agents are given below;
1. It should not degrade the product.
2. It should be compatible with the equipment.
3. It should not cause environment hazardous.
4. It should not be a contaminant of subsequent product.
5. It should easily removable and easily available and non toxic.

CLEANING AGENT
 Organic Solvents, including solvents such as acetone,
methanol, and ethyl acetate, are most commonly used. Water
serves as a solvent and a s a medium for other functional
processes, including hydrolysis, emulsification, and dispersion.
 “Surfactant" is short for "surface active agent. " Surfactants
used for cleaning generally have a hydrophilic polar end and a
lipophilic nonpolar end. The function of a surfactant is for
wetting surfaces (of both the residue and the surface to be
cleaned), solubilization, emulsification, and dispersion.

CLEANING AGENT
 Chelants are products like EDTA (ethylenediaminetetraacetic
acid), NTA (nitrilo triacetic acid), and certain polyphosphates
(like sodium hexametaphosphate) that chelate or tie up certain
metal ions in aqueous solution.
 Chelants can be important for any cleaning operation where
hard water ions (calcium and magnesium) are present. The
presence of chelants may also help remove trace amounts of
iron from the system, thus reducing any tendency for a stainless
steel system to rouge.

SELECTION OF CLEANING METHOD
 Manual cleaning
 Semi automatic procedures
 Automatic procedures
 CIP (Clean-in-place)
 COP (Clean-out-of-place)

Manual Cleaning Method
 Difficult to validate
 Most extensive and elaborate cleaning procedures are required.
 A high quality and extensive training program is required.
 The risk involved in manual cleaning processes is taken care of
with following:
 Proper washroom design with drying, protection and storage
requirement.
 Detailed cleaning SOP
 Training / Qualification of cleaning operators

Clean-In-Place (CIP) Method
 Cleaning of the equipment is performed in place without
disassembling
 Cleaning process may be controlled manually or by an
automated program.
 Very consistent and reproducible cleaning method.
 Can be validated readily.
 Being a closed system visual inspection of all components is
difficult.

Clean-Out-Of-Place (COP) Method
 Cleaning of disassembled equipment is performed in a central
washing machine.
 The washing machine also requires validation such as the
temperature, ultrasonic activity, cycle time, cleaning operation
sequence, detergent quantity dispensed etc.

SAMPLING METHODS FOR CLEANING VALIDATION
There are mainly two types of sampling,
A) Direct sampling B) Rinse sampling
A) Direct sampling :
 The materials used for sampling are very important, the
sampling materials and the sampling medium affects the
samples to be recovered so they should be suitable for use.
 It is important that the sampling materials and the medium
used are satisfactory and does not affect the sample recover.

Swab sampling
 It is also know as direct surface sampling method. This method
is based on the physical removal of residue left over on a piece
of equipment after it has been cleaned and dried.
 A swab wetted with a solvent is rubbed over a previously
determined sample surface area to remove any potential residue,
and thereafter extracted into a known volume of solvent in
which the contaminant active ingredient residue is soluble.
 The amount of contaminant per swab is then determined by an
analytical method of adequate sensitivity.

Advantages
 Direct evaluation of surface contamination.
 Insoluble or poorly soluble substances may be physically
removed from the equipment surfaces.
 Hard-to-clean but accessible areas are easily incorporated into
the final evaluation.
Disadvantages
 Difficult to implement in large-scale manufacturing equipment.
 Extrapolation of results obtained for a small sample surface area
to the whole product contact surface area.

B) Rinse sampling (indirect method)
 The active ingredients and the residues have been checked
in the rinse samples which are used for cleaning.
 This method is based on the analytical determination of a
sample of the last rinsing solvent (generally water) used in
the cleaning procedure. The volume of solvent used for the
last rinse must be known to allow for the quantitative
determination of the contamination.

Advantages
 Ease of sampling.
 Evaluation of entire product contact surface.
 Accessibility of all equipment parts to the rinsing solvent.
 Best fitted to sealed or large scale equipment and equipment which
is not easily or routinely disassembled.
Disadvantages
 No physical removal of the contaminant.
 The rinsing solvent may not reach inaccessible or occluded part of
equipment.
 Use of organic solvents for water insoluble materials.

SAMPLE ANALYSIS
 There are many analytical techniques available that can be used
in cleaning validation
 The Basic Requirements for the Analytical Method.
1. The sensitivity of the method shall be appropriate to the
calculated contamination limit.
2. The method shall be practical and rapid, and, as much as possible
use instrumentation existing in the company.
3. The method shall be validated in accordance with ICH, USP and
EP requirements.
4. The analytical development shall include a recovery study to
challenge the sampling and testing methods.

SAMPLE ANALYSIS
There are two methods:
1. Specific method
2. non-specific method
Specific method
 It is a method that detects a unique compound in the presence of
potential contaminants.
 Ex: HPLC. Non-specific methods are those methods that detect
any compound that produces a certain response.

SAMPLE ANALYSIS
Non-specific method
 It detects any compound that produces a certain response.
 Some examples of nonspecific methods are Total Organic
Carbon (TOC), pH, Titration, and, conductivity.
 The sensitivity of the method shall be appropriate to the
calculated contamination limit.
 The method shall be practical and rapid, and, as much as
possible use instrumentation existing in the company.

METHOD VALIDATION
 Analytical methods used for measuring residues in cleaning
validation protocols should themselves be validated.
 This validation usually means following standard industry
practices for the validation of analytical methods, including
evaluation of specificity, linearity, range, precision, accuracy,
and LOD/LOQ.

METHOD VALIDATION
Specificity
 Specificity is a measure of the validity of the result based on
expected interferences. In other words, one needs to confirm
whether or not the method can unequivocally measure the target
species in the presence of possible interferences. Methods such as
HPLC are generally considered specific. For cleaning processes,
this means that any HPLC procedure should be evaluated to see
whether possible residues from the cleaning agent interfere with
the assay. Interferences may include changes in retention time,
peak height, or peak shape. If cleaning agents are found to
interfere in an HPLC assay, the object should be to modify that
assay such that the cleaning agent no longer interferes.

METHOD VALIDATION
Range
 Range is a series of values of the measured species or property
over which the analytical procedure was evaluated. It is only
necessary to assure that the procedure is valid over a range of
expected values. For example, if the calculated acceptance limit
for the analytical sample is X ppm, then one might want to
evaluate a range from approximately 0.2 X to 1.0 X. On the other
hand, if expected results (perhaps based on prequalification
studies) are to be in the 0.1X to 0.3X range, then validation of a
range of 0.05X to 0.5X may be justified. Determining of the
extent of a valid range for the assay is a matter of risk assessment
and will depend on the degree of confidence and expected
consistency in any prequalification analytical studies.

METHOD VALIDATION
LOD / LOQ
 LOD is the assay value at which it is still possible to say that the
material is present, but it may be not possible to quantify with a
specific value. LOD is typically estimated by several techniques.
For example, for chromatographic techniques, LOD is estimated
at three times the standard deviation of a baseline response. Values
that are below the LOD are generally reported as < LOD. LOQ is
the lowest assay value for which a reasonable confidence exists
that the value is precise. For chromatographic procedures, the
LOQ can be estimated as 10 times the standard deviation of the
baseline noise. The LOQ can also be determined experimentally;
as a practical matter, it can be considered the lower limit of the
validated range of the assay.

METHOD VALIDATION
Linearity
 Linearity refers to the characteristic of the relationship of the
measured property to the level of analyte present. Linearity is
an indication that the measured signal is directly proportional to
the concentration of the analyte over the range.
Accuracy
 Accuracy refers to the trueness of the measurements to known
values. This is determined by analyzing known standards.
There is no "magic number" for acceptable accuracy. However,
more accurate methods are preferred over less accurate
methods.

METHOD VALIDATION
Precision
 Precision refers to the reproducibility of the method and is
often measured by standard deviation.
 Simple precision is the reproducibility of the results in the
same lab over a series of replicate assays using the same
operator, the same equipment, and usually on the same day.
 Intermediate precision is the reproducibility of results in the
same lab using different operators, different pieces of
equipment, and generally done on different days.

VALIDATION PROTOCOLS SHOULD CONTAIN
1. Purpose of the validation study
2. Responsible person for validation study, like performer and
approving authority
3. Full description of equipment to be used in cleaning which
include list of equipment, make model, capacity
4. The cleaning cycle and their frequency for any equipment
before and after use
5. Detailed list of all critical steps to be monitored

6. Selection of cleaning agent with all detail like solubility of
material to be cleaned, safety product removal limit,
minimum temperature and volume of cleaning agent
7. Detailed Sampling procedure
8. Type of sampler
9. Volume/quantity of sample
10. Containers for sample
11. Sampling location
12. Sample handling

13. Sample storage
14. Analytical testing procedure with LOD (limit of detection)
15. The rational acceptance criteria with margin of error and
sampling efficiency
16. Change control
17. Approval of protocol before the study
18. Deviation

CHANGE CONTROL & REVALIDATION
 Once the cleaning process is validated, it should be operated under
change control procedures, and the validation should be confirmed
on a regular basis. The cleaning validation master plan should
specify that validated cleaning procedures are operated under
change control. A change control system is in place to ensure that
all changes that might impact the cleaning process are assessed
and documented. Minor changes or changes having no direct
impact on final or in-process product quality should be handled
through the documentation system.
 The revalidation is usually done on a regular basis, frequency
should be specified in the cleaning validation master plan.

CHANGE CONTROL & REVALIDATION
 On the specified frequency, all data related to the cleaning process
should be evaluated. This may include the following information:
1. All change control done on the cleaning process
2. All change control on the manufacturing process of the product
cleaned:
3. All monitoring data on the cleaning process
4. All QC (quality control) data on products made subsequent to the
cleaning process
5. All QC data on the lots of cleaned product
6. The original report on the initial cleaning validation
It should be noted that before a full revalidation is performed, it is
usually appropriate to investigate the cleaning process to determine
what changes can be made to improve the consistency of that
process.

CLEANING OF EQUIPMENT
There are two types of cleaning equipment
 Type A Cleaning equipment
 Type B cleaning equipment

Type A Cleaning equipment :
 The equipment should be dismantled first and the dismantled parts
shall be transferred to the washing area.
 In the washing area all the dismantled parts of the equipment shall be
cleaned with the cleansing agent sodium laurel sulphate (or other
cleaning aids if required) as per the SOP mentioned mentioned under
the respective equipment SOP for the cleaning procedure.
 The parts that cannot be dismantled shall be cleaned in their
respective place as per their specifications provided in the standard
operating procedure A wash/ rinse water sample can be collected
after visually verifying the equipment by the QA personnel.

TYPE A CLEANING IS APPLICABLE FOR THE FOLLOWING :
 Product to product changeover
 Batch to batch changeover of sample product but change in
colour or flavour
 Batch to batch change over of sample product from higher to
lower strength
 After completion of 5 consecutive batches or completion of
120 hours
 After major breakdown where contact parts are contaminated

CLEANING OF TYPE -B EQUIPMENT
 The equipment shall be cleaned without dismantling the
equipment with vacuum cleaner.
 The equipment shall be cleaned and mopped with clean
moist linin cloth and later with a dry cloth

TYPE B CLEANING IS APPLICABLE FOR THE
FOLLOWING
 Batch to batch change over of the same product of the same
strength, colour and flavour
 Batch to batch changeover from low strength to higher strength
 After completion of the batch
 After minor breakdown, where the contact parts are not disturbed
or contaminated
 Cleaning is done after the completion of preventive maintenance
work
 If contact parts are not touched /disturbed this type of cleaning is
recommended

GENERAL INSTRUCTIONS TO CLEAN EQUIPMENT
 All the equipment shall be cleaned as per the SOP of cleaning of
equipment using nylon brush and cleaning agent with portable raw
water
 Use compressed air to dry the equipment
 After completion of cleaning the equipment shall be marked
"cleaned"
 Before using any equipment examine the equipment visually
whether it is clean if not re cleaning procedures should be adopted
 Hold time for unclean equipments shall be 72 hours where as for
Clean equipments it is 5 days

CLEANING OF FACILITIES
 Every pharmaceutical site needs good hygiene and
sanitation over 24 hours and 365 days a year.
 70% of the failure in sanitation and hygiene can be
attributed to the lack of orientation and inadequate
training.
 It is very commonly observed that the cleaning records
are filled mechanically.

 Following are the Critical Areas which needs active attention for
Cleaning and sanitation
1. Store areas where Excipients such as sugar, lactose and starch are
stored in large quantities
2. Liquid Processing areas
3. Equipment washing areas
4. Water handling systems
5. Containers /closures cleaning and storage areas
6. Personal Wash Rooms and Primary Change Rooms
7. Refreshment and Lunch rooms
8. Materials receiving areas

9. Sanitary and Product drain lines
10. Air handling systems
11. Sampling and dispensing areas
12. Service areas
13. Processes involving high dusting
14. Packaging areas
15. Corrugated Boxes storage area
16. Open electrical wirings, electrical lamps, and open service lines
17. Ledges and platforms

CLEANING IN PLACE
 Clean-in-place (CIP) is a method of cleaning the interior
surfaces of pipes, vessels, process equipment, filters and
associated fittings, without disassembly.
 Up to the 1950s, closed systems were disassembled and
cleaned manually.
 The advent of CIP was a boon to industries that needed
frequent internal cleaning of their processes.
 Industries that rely heavily on CIP are those requiring high
levels of hygiene, and include: dairy, beverage, brewing,
processed foods, pharmaceutical, and cosmetics.

CLEANING IN PLACE
 The benefit to industries that use CIP is that the cleaning is
faster, less labor- intensive and more repeatable, and poses less
of a chemical exposure risk to people.
 CIP started as a manual practice involving a balance tank,
centrifugal pump, and connection to the system being cleaned.
 Since the 1950s, CIP has evolved to include fully automated
systems with programmable logic controllers, multiple balance
tanks, sensors, valves, heat exchangers, data acquisition and
specially designed spray nozzle systems. Simple, manually
operated CIP systems can still be found in use today.

CLEANING IN PLACE
 Depending on soil load and process geometry, the CIP design
principle is one of the following:
1. Deliver highly turbulent, high flow-rate solution to effect good
cleaning (applies to pipe circuits and some filled equipment).
2. Deliver solution as a low-energy spray to fully wet the surface
(applies to lightly soiled vessels where a static spray ball may be
used).
3. Deliver a high energy impinging spray (applies to highly soiled or
large diameter vessels where a dynamic spray device may be used).
4. Elevated temperature and chemical detergents are often employed to
enhance cleaning effectiveness.

Cleaning Validation Ppt Pharmaceutical validation

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