Cleaning Validation ProtocolRevision HistoryDocument No.:CVP/
001
Effective Date:
Revision No: R0Supersedes: N/APage No.:Page 1 of 1
COMPANY LOGO
COMPANY NAMECompany Address
CLEANING VALIDATION PROTOCOL
FOR
AT:
INDEXS. No.ContentPage No.
1. Preapproval of Protocol3 of 15
2. Introduction4 of 15
3. Objective4 of 15
4. Scope4 of 15
5. Responsibilities5 of 15
6. Protocol Training Record6 of 15
7. Product Profile6 of 15
8. Equipment Description7 of 15
9. Methods of Cleaning7 of 15
9.1 Cleaning Procedures7 of 15
9.2 Materials and Equipments used for cleaning8 of 15
9.3 Cleaning SOP Index for each equipment8 of 15
10. Sampling Method9 of 15
10.1 Selection of Sampling Method9 of 15
10.2 Scientific rational for selecting Sampling Points9 of
15
10.3 Visual Inspection9 of 15
10.4 Swab Sampling for Chemical Analysis of API9 of 15
10.5 Sampling Patterns10 of 15
10.6 Swab sampling for Microbial analysis10 of 15
10.7 Swab sampling Location11 of 15
11. Analytical Procedure12 of 15
12. Establishment of Acceptance Criteria12 of 15
12.1 Visual Inspection12 of 15
12.2 Active Residue12 of 15
12.3 Rational to Calculate Maximum Allowable Carry-Over Taking
the Worst-Case12 of 15
12.4 Rational to Calculate Maximum Allowable Carry-Over Taking
the 10 ppm Criteria13 of 15
12.5 Establishment of Acceptance Limits13 of 15
12.5.1 Acceptance Limits per Equipment (ALE) for API13 of 15
12.5.2 Acceptance Limits per Swab (ALS) for API13 of 15
12.6 Acceptance Limits for Microbial Bio-burden14 of 15
13. Acceptance Limits for the Cleaning Agent14 of 15
14. Hold Time Study15 of 15
15. Revalidation Criteria15 of 15
1. Preapproval of Protocol:Signing of this Protocol indicates
agreement with the Cleaning validation approach established for .
Further, if any changes in this Master Plan would be required, it
will be revised and duly approved.
Compiled By:
Functional areaNameDesignationSignatureDate
Quality Control
Production
Quality Assurance
Reviewed and Approved By:
Functional areaNameDesignationSignatureDate
Head-Quality Control
Head-Production
Quality Assurance
Authorized By:
Functional areaNameSignatureDate
Head-Quality Assurance
2Introduction:
Cleaning Validation in the context of manufacture of the solid
oral products at may be defined as:The process of providing
documented evidence that the cleaning method of the equipments and
ancillary utensils employed within the facility consistently
controls potential carryover of product (including intermediates
and impurities), cleaning agents and extraneous material into
subsequent product to a level which is below predetermined levels.
(Source: APIC, September 1999)It is necessary to Validate Cleaning
procedures for the following reasons:a) It is a customer
requirement - it ensures the safety and purity of the product.b) It
is a regulatory requirement in Active Pharmaceutical Ingredient
product manufacture.c) It also assures from an internal control and
compliance point of view the quality of the process.
3Objective:
The objective of this protocol is; Objective of Cleaning
Validation is to establish and assure with documented evidence that
the cleaning procedures used after manufacturing of is effective
and consistently performs as expected and produce a result that
meets a predetermined acceptance criteria when manufactured. To
provide documented evidence through the scientific data to show
that the cleaning procedure used after manufacturing of Tablet is
effective and consistently performs as expected and produce a
result that meets a predetermined acceptance criteria when
manufactured. To establish that the cleaning process shall provide
a high degree of assurance for removal of residues of the last
manufactured product, so that those residues are not transferred to
the subsequently manufactured product. To prove that equipment is
consistently cleaned of product to an acceptable level to prevent
contamination and cross-contamination
4Scope:
The scope of this protocol is applicable for the Cleaning
validation of Also, to evaluate the acceptability of cleaning
procedure used in cleaning of equipment using well-established
analytical and microbiological method to determine the chemical and
microbiological residue after cleaning of the equipment. This will
also cover the responsibilities, sampling plan, acceptance
criteria, re-validation criteria, and change control procedure.
This protocol is applicable for .
5Responsibilities:
5.1Quality Assurance:
5.1.1 To prepare the Cleaning Validation Protocol.
5.1.2 To review the Cleaning Validation Protocol.
5.1.3 To monitor cleaning activities.
5.1.4 To collect swab/rinse samples from cleaned equipment.
5.1.5 To review analytical reports.
5.1.6 To prepare and review cleaning validation report.
5.2Production:
5.2.1 To review the Cleaning Validation Protocol.
5.2.2 To provide details of equipments.
5.2.3 To get the equipments cleaned by trained operators.
5.2.4 To schedule cleaning validation program.
5.2.5 To maintain log-books for equipment cleaning.
5.2.6 To review cleaning validation report.
5.3Quality Control:
5.3.1 To review the Cleaning Validation Protocol.
5.3.2 To analyze the swab/rinse samples collected for cleaning
validation.
5.3.3 To compile the analytical data.
5.3.4 To review cleaning validation report.
5.4Quality Control (Microbiology):
5.4.1 To review the Cleaning Validation Protocol.
5.4.2 To collect Microbiological samples from cleaned
equipment.
5.4.3 To analyze the cleaning validation samples.
5.4.4 To compile the Microbiological data.
5.4.5 To review cleaning validation report.
5.5Head Quality Assurance:
5.5.1 To review and to approve cleaning validation protocol and
report.
6Protocol Training Record:
All the personnel involved in the cleaning validation activity,
sampling and testing of cleaning validation samples must be
appropriately trained in their assigned job responsibilities and on
the Cleaning validation protocol. Personnel or operator who
performs cleaning routinely should be trained and should be trained
and should be effectively supervised. Record the training details
of the persons involved in the sampling and testing.
7Product Profile:
7.1 is the existing product of the of .
7.2
7.3
7.4
7.5 Chemical Skeletal Structure the API :
7.6
7.7
7.8 Three batches of the product shall be validated for
Cleaning.
8Equipment Description:
Following Equipments of same design and operating principles
shall be deployed for cleaning validation of the three batches of
.
S. No.Name of EquipmentCapacityID NumberSurface Area
(cm2)**Surface Area (cm2)
8.1.
8.2.
8.3.
8.4.
8.5.
8.6.
** Surface Area + 10% of Surface Area
9Methods of Cleaning:
9.1 There are three types of cleaning procedures deployed at
:
a) Type A For batch to batch changeover. End of the shift
cleaning or whenever required. Change over to ascending strength of
same colour and flavour.b) Type B During changeover of product with
different API, colour/flavour and products having same
API/colour/flavour but with descending strengths. After five
consecutive batches of same product. Equipment kept in ideal
condition for more than 48 hours. Equipment kept in idle condition
for more than 7 days subsequent to Type B Cleaning. After carrying
out preventive maintenance or any major maintenance activity.c)
Type C On Type B cleaned equipment just prior to use, when required
to be used within 7 days from the date of Type B cleaning.Note:
Cleaning Validation is required only in the scenario of Type B
cleaning, as it is done after product to product changeover and
cleaning process deploys water and detergent.
9.2 Materials and Equipments used for cleaning:
9.3 a) Purified Waterb) Tap waterc) Vacuum Cleanerd) Scrubbere)
Dry sponge or lint free cloth.f)
9.4 Cleaning SOP Index for each equipment:
Sr. No.Name of EquipmentID NumberCleaning SOP Number
9.3.1.
9.3.2.
9.3.3.
9.3.4.
9.3.5.
9.3.6.
NOTE:Equipments shall be cleaned as per the respective cleaning
SOPs followed during product changeover only . Swabs of the cleaned
equipments shall be taken as per the sampling points given in the
DRS.
10Sampling Method:
10.1Selection of Sampling Method:
Swab sampling shall be considered as sampling method.
Justification for swab sampling: Looking to the Design and Size of
equipment, swab sampling shall be considered main method for
validation; however, rinse will also be taken wherever necessary.
Most difficult to clean locations are selected for sampling to
determine the efficacy of cleaning. Advantage of swab sampling:
Direct evaluation of surface contamination Insoluble and poorly
soluble substance may be physically removed Hard to clean but
accessible areas are easily incorporated in final result.
10.2Scientific rational for selecting Sampling Points:
The product contact surface area which is most difficult to
clean shall be selected as sampling point. The location selected
for swabbing are generally those locations that are most difficult
to clean representative of different materials and representative
of different functional locations (side corners, agitator, blades
etc.). If these locations are swabbed and if residues in these
materials are acceptable then residues on another location shall
also be acceptable. Performing swab on these locations and
materials can be helpful in terms of providing higher assurance in
validation results.
10.3Visual Inspection:
After cleaning of the equipment visual inspection shall be done.
To carry out a visual inspection, use a torch if required and a
mirror (attached to stainless steel rod) to inspect the surface of
equipment. This should be done under viewing conditions (Lighting,
angle, Distance), that simulate the viewing of Equipment.
10.4Swab Sampling for Chemical Analysis of API:
Description of swab:
MakeTexwipe Swab ,USA
ModelTX714A
Head MaterialKnitted Alp halite Polyester
Handle MaterialPolypropylene
Swab samples shall be taken after the final cleaning of the
equipment, once the equipment qualifies the visual inspection test.
The swab shall be dipped in swabbing media; i.e. in 50ml Test-Tube.
Swab samples from different areas of equipment shall be collected.
Swab area shall be measured for swabbing.
Sampling error: During swab sampling following care to be taken:
area of sampling (should not be less than 100 cm2), apply proper
force during collection of sample to avoid any sampling errors.
Sampling area: 10 x 10 cm. = 100 cm2 or equivalent (for the
parts, where 100 cm2 is not available as whole)
10.5Sampling Patterns:
Wipe the defined area in zigzag directions as shown in the
figure. Apply only one time at a surface for one time only. Collect
the swab by application of normal force.Note: Avoid lifting the
swab stick from contact surface during collection of swab.Refer the
diagram to collect the sample-using swab. Start Start End
10cm OREnd 10 cm 10 cm (Direction of swabbing strokes)
Handling of swab Samples: Swab and Swabbing Media shall be
prepared by quality control, The test tubes shall be covered with
paraffin film, proper precaution shall be taken during handling of
swab. After swabbing, each sample shall be placed inside the test
tube duly labelled and covered with paraffin film and should be
sent to QC Laboratory for testing of determination.
10.6Swab sampling for Microbial analysis:
Sterile hand gloves and face mask shall be worn before taking
the swab. Sterile swab shall be from the test tube and dipped into
0.9% sterile saline solution. Now the Swab shall be stroked over a
5 x 5 cm (or equivalent) of the product contact surface. The
strokes should be as per the procedure for chemical swab only.
Immediately the Swab shall be processed as per the procedure for
Microbial Testing.
10.7Swab sampling Location:
Prior to swab sampling, cleaned equipment shall meet Visual
Clean criteria. Sampling shall be carried out as per current
version of SOP. Chemical and microbial sampling location shall be
different from each other. The locations from where, swab sample is
to be taken is identified are below:
Chemical swab samplingMicrobial swab sampling
Sr. No.EquipmentLocationNo. of swab locationsLocationNo. of swab
locations
1
2
3
4
5
6
11Analytical Procedure:
Analytical methods for Specific analysis were validated as per
Analytical Method Validation Protocol. Validated methods shall be
employed to analyse the cleaning validation samples.
12Establishment of Acceptance Criteria:
The cleaning procedure shall be considered validated, when the
acceptance criteria, as specified in the protocol, is met.Failure
of individual sampling points will not necessarily mean that the
cleaning method is inadequate. Each deviation shall be investigated
and based on the investigation, corrective actions will be taken
and that my require further follow-up or further validation.
12.1Visual Inspection:
Equipment should be visually clean and dry and must contain NO
visible residues.
12.2Active Residue:
Calculation of active residue after cleaning shall be based on
product contact surface area. This approach is based on acceptable
daily intake. Based on the Acceptable Daily Intake and Safety
Factor (1000 for Oral dosage forms) the Maximum Allowable
Carry-Over (MACO) is calculated; i.e. it is assumed that only a
fraction (1/1000) of the smallest daily dose of Product-A can be
carried-over to the maximum allowable daily dose of Product-B
manufactured in the same equipment train.
12.3Rational to Calculate Maximum Allowable Carry-Over Taking
the Worst-Case:
The Maximum Allowable Carry-Over (MACO) shall be calculated the
following factors:
STD(A):Single Therapeutic Dose of Product A (in mg).
SBS(B):Smallest Batch Size of Product B (in mg).
SF:Safety Factor (constant) = 1000 for solid dosage forms
LDD(B):Largest Daily Dose of Product B (in mg).
Thus, the formula to calculate MACO is:
MACO for a specific Equipment Train = STD(A) x SBS(B)
SF x MDD(B)
12.4Rational to Calculate Maximum Allowable Carry-Over Taking
the 10 ppm Criteria:
Maximum Allowable Carry-Over (MACO) can also be calculated for
the products manufactured in the Tablet section using the following
formula:
Starting point is the amount of contaminant (Product-A) accepted
as being taken with the "next" Product-B. The approach is to regard
the active ingredient of the Product-A as the contaminant to look
for. For solids, an active ingredient intake of 1/1000th of the
lowest therapeutic dosage of that active is usually regarded as
harmless. The maximum amount of contaminant Product-A allowed to be
taken in per day is STD (A) / 1000 per day. This means that with
the daily intake of the next product, the maximum allowed of
contamination is 1/1000th of the daily therapeutic dosage of the
contaminant, which has been mentioned in the Master Plan as Safety
Factor. To be on the safe side, the maximum daily intake of the
next product is considered. In case of 10 ppm (or 10 mg/ kg)
criteria, the STD (A) is considered to be 10 mg/ kg, regardless of
the actual amount of dose. Thus, the quantity Product-A allowed in
a single dose of Product-B is:Q = 10/ [1000 x MDDB (in numbers)] =
0.01/ MDDB (in numbers) This quantity is for one dose unit of
Product-B. For the entire batch of Product-B is,MACO (10 ppm) = Q x
SBS (B) / One Dose Unit of Product-B (Subject to Recovery
Factor)Where SBS (B) is the Smallest Batch Size of product B.
(Refer Annexure- VII)
Based on the current scenario, we shall be taking 10 ppm
criteria under consideration as the acceptance limit obtained from
MACO index is more than the acceptance limit obtained from the
10ppm criteria.
12.5Establishment of Acceptance Limits:
12.5.1Acceptance Limits per Equipment (ALE) for API:
On getting the MACO value for the whole equipment train, an
acceptance limit of maximum allowable carry-over per equipment is
required to be calculated for individual equipments of the train.
The calculations are as follows:
ALEMACO x Surface Area of individual equipment
Total Surface Area of all equipment in the train
12.5.2Acceptance Limits per Swab (ALS) for API:
On getting the ALE value, acceptance limit per swab is
calculated, to get an acceptable quantity maximum allowable
Carry-Over per swab. The calculations are as follows:
ALSALE x Swab Surface Area
Note: The swab surface area is considered as 10 x 10 cm or
equivalent.
Surface Area of individual equipment
Acceptance Limit per Swab for Chemical Analysis =
12.6Acceptance Limits for Microbial Bio-burden:
Swab samples for Microbial Analysis shall be collected from
product contact surface area immediately after the completion of
cleaning activities and after specified hold time period of total
aerobic microbial count. The limits for microbiological bio-burden
criteria for product contact surface area is as follows:
Product Equipment Contact SurfaceMicrobiological Bio-burden
(cfu/ 25cm2)Corrective Action(If the counts go beyond limit)
Total Plate CountMould and Yeast
Alert LevelAbsent No action required.
Action LevelAbsent Investigate possible causes Perform
re-cleaning Perform extra microbial testing
LimitAbsent
13Acceptance Limits for the Cleaning Agent:
To establish the effectiveness of cleaning process to remove the
cleaning agent; i.e. , the acceptance limits shall be prepared
based on the toxicological data of the . The calculations are as
follows:NOEL= LD50 (of Detergent) x 70kg/2000
Maximum Allowable Carry-Over for Detergent (MACOD)= NOEL (of
Detergent) x SBS/SF x MDDB Where,NOEL: No Observed Effect
Level2000: an empirical constantLBSB= Largest Batch Size of Product
BMDDB: Maximum normal daily dose for next prodSafety factor: 1000
(Constant for Oral Solid Dosage)
Thus, the Acceptance Limit per Swab (ALS) =
14Hold Time Study:
To establish the effectiveness of cleaning, equipment shall be
kept idle for 72 hrs in controlled conditions. To establish the
expiry of cleaning in view of microbiology, equipment shall be kept
idle after cleaning for 72 hrs and microbiological swab shall be
taken and analyzed. This shall be considered as worst case and
microbial load should remain within the limits.
15Revalidation Criteria:
Cleaning procedure should only need to be validated once.
Periodic monitoring using swab samples is required to ensure
compliance. Revalidation shall be done when Change in cleaning
procedure Change in cleaning agent used for cleaning Change in
minimum batch size and lowest dose of the product i.e. Change in
MACO limit Major Modification in processing equipment Any
regulatory requirements
Note: Any change must be formally requested, documented with
Change Control. The likely impact / risk of the change on the
product must be assessed and the need for the extent of
re-validation should be determined.
Cleaning Validation ProtocolFor Document No.:CVP/001
Effective Date:
Revision No: R0Supersedes: N/APage No.:Page 2 of 15
End of DocumentRevision No.Date of ReviewChangesReviewed By
R0 First issue.Sandeep Mehra