Purpose
To lay down the procedure for Cleaning
Validation of manufacturing equipment’s. This SOP describes the validation of
cleaning procedures for the removal of contaminants associated with the
previous products, residues of cleaning agents as well as the control of
potential microbial contaminants.
Procedure
Principle
Products can be contaminated by other
products, by cleaning agents, by microorganisms or by other material (e.g.
air-borne particles, dust, lubricants, raw materials, auxiliaries). In many
cases, the same equipment may be used for processing of different products. To
avoid contamination of the product, adequate cleaning procedures are essential.
Cleaning Validation is documented
evidence that an approved cleaning procedure will provide equipment which is
suitable for processing of products.
Objective of the Cleaning Validation is
the confirmation of a reliable cleaning procedure so that the analytical
monitoring may be omitted or reduced to a minimum in the routine phase.
Guidelines for Cleaning
Validation:
It deals with the validation of
equipment cleaning procedures used in the pharmaceutical industry to prevent
cross-contamination or adulteration of drug products.
Active ingredients: The most obvious
area for evaluation in cleaning validation is removal of active ingredients
from the equipment. This evaluation can be carried out by a number of methods,
but all have in common the need for adequate analytical methodology and the
establishment of practical yet meaningful acceptance criteria for residuals.
Cleaning Validation Approach:
- All new as well as existing equipment shall be validated with respect to cleaning.
- Validation test shall be run according to approved protocol detailing methods, condition, procedure test and acceptance criteria.
- Change control systems at the plant should cover cleaning agents so that the need for revalidation can be assessed whenever cleaning agents are changed
General:
- Normally cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, are mixing shaft, heating elements etc.
- Generally, in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.
- Several questions should be addressed when evaluating the cleaning process. For example:
- At what point does a piece of equipment or system become clean?
- What does visually clean mean?
- Does the equipment need to be scrubbed by hand?
- What is accomplished by hand scrubbing rather than just a solvent wash?
- How variable are manual cleaning processes from batch to batch and product to product?
- What is the most appropriate solvent or detergent?
- Are different cleaning processes required for different products in contact with a piece of equipment?
- How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
- Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a Validation Programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria.
- At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.
- Control of change to validated cleaning procedures is required. Revalidation should be considered under the following circumstances.
- Re-validation in case of changes to equipment, products or process,
- Documentation:
- A Cleaning Validation Protocol is required for laying down the procedure on how the cleaning process will be validated. It should include the following but not limited to:
- The objective of the cleaning validation process.
- Scope of Validation activities
- Responsibility for performing and approving the validation studies.
- Validation Team.
- Cleaning Validation approach-
- Product Matrix
- Selection of Products
- Selection of Equipment’s
- Process Overview
- Pre cleaning validation requirements
- Precaution and Instruction
- Calculation of MACO
- 10 ppm criteria
- Microbial Contamination
- Cleaning Validation Program
- Selection of Cleaning Procedure
- Clean-In- Place (CIP)
- Clean-out-place (COP)
- Manual Cleaning
- Water Quantity
- Selection of Analytical Method
- Analytical Method Validation
- Specificity Potential interferences
- Selection of extraction solvent
- Recovery Study
- Recovery from Spiked plates/ Coupons or different MOC’s
- Recovery correction Factor
- Sampling Plan, type of Sampling and Selection of Sampling Method
- Evaluation of Cleaning Procedures
- Sampling
- Sampling technique for Chemical Analysis
- Sampling technique for Microbial Analysis
- Determination of Sampling Points
- Equipment Hold Time Study
- Testing Procedure
- Acceptance Criteria
- Selection of Worst Case Product Review of Data
- Justification of selection of Worst case
- Solubility
- Calculation of swab Limit
- Revalidation
- Cleaning Validation final report
- The Validation Protocol & reports shall be prepared by QA, reviewed by concerned department and approved by Head QA.
- A final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully. Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined).
- Records should be kept for cleaning performed in such a way that the following information is readily available:
- The area or piece of equipment cleaned,
- The person who carried out the cleaning,
- When the cleaning was carried out,
Equipment:
- The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.
- Dedicated equipment should be used for products which are difficult to remove, for equipment which is difficult to clean, or for products with a high safety risk (e.g. products of high potency which may be difficult to detect below an acceptable limit).
Microbiological
Aspects:
- The existence of conditions favorable to reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.
- The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
- In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.
Analytical
methods requirements:
- The analytical methods should be validated before the Cleaning Validation Study is carried out.
- The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable.
- The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery.
Calculation for
residuals:
Product Residue
Contamination
The rationale for selecting limits of
carryover of product residue shall be logically based on the materials
involved. The limits should be practical, achievable and verifiable. On the
basis of following criteria acceptance limits i.e. Maximum Allowable Carry Over
(MACO) shall be established:
10 PPM Criteria:
As per this criterion, not more than 10
ppm of any product will appear in another product.
The following equation is used to
calculate the limit of product ‘A’ if the next product on the production
schedule is product ‘B’.
Maximum Allowable Carry Over (mg per
batch) = 0.00001(mg/mg) X BS in mg
Where,
0.00001 mg of product ‘A’ per 1000000mg
of the product ‘B’
BS: Batch size of the next product in
mg.
On the basis of 10 ppm criteria the
MACO limit shall be calculated.
After establishing MACO (with minimum
value) the swab limits and / or rinse limits shall be established with respect
to total product contact surface area and
total rinse volume respectively.
MACO X 100
Swab Limit (drug in mg per 100 cm2
swabbed area) = ----------------------
TS
Where,
100: Sampled swab area (100 cm2)
TS: Total product contact surface area
(cm2)
Visually Clean
Criteria
No quantity of residue should be
visible on the equipment after cleaning procedure is performed.
Active ingredient in most of the
products is visible at the approximately 100 µg per 10 cm sq. of surface area.
Below this level the residue is not visible to human eye.
Stringent Acceptance criteria shall be
selected as worst case either from 10 ppm criteria. LOQ shall be considered
during selection of acceptance criteria.
Calculation of
amount of residue present in rinse & swab:
Rinse:
Content / residue of previous product
in the rinse is reported in PPM by Quality Control.
It is to be converted in to milligram
by multiplying the QC results with quantity of rinse sample in kg.
The resultant value is the residue of
previous product in milligram from entire equipment / part of equipment
cleaned.
For possible contamination per 10 cm2
in next product, the resultant value is multiplied by 10 and divided by surface
area (in cm2) of the equipment / part of equipment cleaned which is common for
the two products.
Example:
Residue of previous product (QC
results) = 4.86 ppm
Quantity of rinse = 30 Liter
Content / residue of previous product
in mg = 4.86 x 30 =145.80 mg
Surface Area =
24193.50 cm2
Possible contamination in next product
per 10 cm2
145.80
=
-------------------- x 10 = 0.06026 mg / 10 cm2
24193.50
Swab:
Content / residue of previous product
in the rinse is reported in µg per 10 cm sq by Quality Control.
It is to be converted in to milligram
by dividing the residue in µg by 1000. This is the possible contamination in
next product in mg per 10 cm2.
Example:
Residue of previous product (QC
results) = 12.42 µg
Possible contamination in next product
per 10 cm2
12.42
=
---------------------- = 0.01242 mg
/10 cm2
1000
% Recovery
Factor shall be applied to calculated results to get the actual residue:
100
Recovery Factor = ---------------------------------------
%
Recovery (From AMV)
Actual residue = Calculated result X
Recovery factor
Procedures for
cleaning Validation Based on Bracketing & worst case Rating:
- The cleaning processes of multiple product equipment are subject to requirements for cleaning validation. In order to minimize the amount of validation requirement a worst case approach for the validation can be used. Collect the following information before starting cleaning validation.
- Materials needed to be cleaned from the equipment i.e. active ingredient.
- Equipment chain used during manufacturing of a particular product.
- A list of product that are manufactured using above chain of equipment in the facility.
- Data of surface area of each piece of equipment that is in contact of the product, used in the manufacturing of the product(s) at the formulation site with respect to the batch size.
- For each product collect the following details
- Batch size in Kg.
- Active ingredient
- Smallest batch manufactured
- Solubility in water.
- Product contact surface area of each piece of equipment in the facility.
Worst Case
Rating: Decide the worst case product(s) based
on the following:
Select the worst case product based on
lowest strength (high potency) lowest solubility of its active ingredient in
water from the product matrix and followed by difficulty in cleaning.
Select worst case next product based on
the highest ratio of batch
Worst Case Rating shall be as follows:
Potency (TD)
>Solubility > Difficult to clean
Methods of
evaluation: There several reasonable ways to
evaluate the effectiveness of cleaning procedures and the choice of one over
the others should be based on the unique characteristics of the equipment and
product(s) involved.
Swab test: After cleaning the equipment, product
contact surfaces can be swabbed to evaluate surface cleanliness. Swabs used
should be compatible with the active, in that they should not interfere with
the assay, should not cause degradation of the compound, and should allow
extraction of the compound for analysis. The solvent used for swabbing should
provide good solubility for the compound and should likewise not encourage
degradation.
Sampling
considerations: The area to be
sampled should be in its final condition, as it would be when ready to use. In
some cases, it is reasonable to swab the entire product contact surface.
However, when this is not reasonable, a known surface area should be tested,
and the approximate overall surface area which is represented by the swab(s)
should be known. The area to be sampled should be selected using judgment about
which areas are most difficult to clean. To ensure accuracy of the overall
procedure, it can be applied to a surface which has been deliberately
contaminated with a known, low level of the active. Obviously, the surface used
for this challenge must be made of the same material as the equipment to be
tested.
Advantage: Advantage of direct sampling of that
areas, hardest to clean and which are reasonable accessible can be evaluated,
leading to establishing a level of contamination or residue per given surface
area. Additionally, residues that are dried out or are insoluble can be sample
by physical removal.
Rinse samples: Sampling and testing rinse samples for
residual active ingredient is commonly used method to evaluate cleanliness the
solvent used should be selected based on the solubility of the active
ingredient or at least provide adequate solubility. If possible, steps should
be taken to ensure the uniformity of the residual material in the rinse prior
to sampling. It is also critical that the volume of rinse solvent used be
controlled. For equipment designed to hold liquids, either the volume of rinse
solvent used should be sufficient to ensure contact with all product contact
surfaces, or the method of introducing the rinse solvent should ensure adequate
contact with all surfaces.
Cleaning Agent: A second important focus of cleaning
validation is the removal of cleaning agents. These are known equipment
contaminants which are added, ironically, to assist in the cleaning operation
itself. In most cases, more than one cleaning agent is approved for use. The
removal of each may have to investigate to ensure that no problems will be
encountered with their use. For this reason, it is prudent to limit the number
of approved cleaning agents to minimum required for effective cleaning in
various situations.
Applications of Sampling Methods
Sampling Method Common applications (processing equipment)
Swab Sample Holding tank of filling machine, Manufacturing &
storage vessels, filter press & Inline homogenizer
Rinse samples Vessels and tanks (including agitators), filter housings
& filling machine
Acceptability
limits:
Determination of acceptability limit is
a critical factor while preparing cleaning validation protocol.
The calculation of acceptable level for
previous product as contaminant is important while determining the
acceptability limit for cleaning validation.
The validation protocol must include
the list of all products manufactured in the equipment/facility and in which
the cleaning validation shall be performed.
Carry-over of product residues should
meet defined criteria; the most stringent limit of the following criteria shall
be considered for carry-over of product residues:
Visual
inspection criteria: No
quantity of residue should be visible to naked eye
on the equipment after cleaning procedures are performed (i.e. less than 100
mcg /25 cm2).
10ppm criteria: Not more than 10ppm of active
pharmaceutical ingredient of previous product is permitted in next product.
Hold Time
Studies
The objective of hold time study is for
establishing time limit between equipment cleaning and reuses it to ensure that
the equipment remains clean till the next use.
Equipment
Holding Studies prior to cleaning
The interval between the end of production
and the beginning of the cleaning process shall be established through
equipment holding studies prior to cleaning.
It is important to consider the effect
that weekends, holidays and delays might have on the cleaning schedule.
To establish the expiry of cleaning in
view of microbiology, equipment shall be kept ideally after 72 hours and
microbiological swab shall be taken and analyzed at different intervals
(initial,24,48,72 hrs.).
Cleaned
Equipment Hold Time Studies
Concerns relative to microbial control
are lessened in the production of non-sterile products but are still important.
Practices which minimize the potential for contamination by ‘objectionable
organisms’ are common in the manufacture of non-sterile formulations.
To establish the expiry of cleaning in
view of microbiology, equipment shall be kept ideally after cleaning for 7 days
and microbiological swab shall be taken
and analyzed at different intervals (0 day, 1 day, 2 day, 3 day, 4 day, 5 day,
6 day and 7 day).
This will be considering as worst case
and microbial load should remain well within limit.
Revalidation
Re-validation shall be performed in
case of any change, (at least the following but not limited to)
Introduction of a new facility,
equipment, process or product.
Change in cleaning procedure.
change in MACO limit and potency of
product.
Change in cleaning agent used for
cleaning.
Major Modification in processing
equipment.
New product/
Equipment Evaluation:
When a new product is introduced in the
plant an evaluation is made to determine if cleaning validation is required. If
the new product carryover limit is above the previously determined carryover
limit and the new product is more soluble and less potent than the target
component of the previous product, then cleaning validation is generally not
required. This will be documented in the cleaning validation plan.
Introduction of any new product in
existing product matrix shall be carried out through New Product/Equipment Evaluation
Sheet.
Review and update the cleaning
validation product matrix before a new product is introduced in production
facility.
Review and update the cleaning
validation equipment train if any change in existing equipment train,
re-validate the cleaning process if required.
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