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Friday, August 22, 2008



No. of Pages No. of Copies
Supersedes the SOP/QA-/QA
Version NO:
Document due for revision :-

1. Introduction: Cleaning Validation or qualification is the generation of documented evidence that demonstrates that a cleaning operation is consistently capable of cleaning tp predetermined levels of cleanliness.It is an important mechanism to protect pharmaceutical products from cross-contamination.
The Liquid manufacturing facility will be validated based on the matrix approach wherein the worst case criteria will be selected.

2. Objective:This exercise aims at validating the Liquid manufacturing facility \ in order to ensure that the cleaning procedures consistently remove residues of pharmaceutical actives from the manufacturing facility and equipment to predetermined levels of acceptability.

This exercise is not applicable to cleaning following non-routine operations such as spillage or breakage during manufacture.

3. Scope:
The procedure followed for cleaning the manufacturing equipment and premises will be validated.The following equipment coming in direct contact with the actives are critical and will be considered during validation:Liquid manufacturing vessel,Peristaltic filling pump.The other equipment used during mfr ,but which do not come in contact with the actives,will not be considered during validation.

4. Validation Team

Name of Persons Department ResponsibilityName
Production Department:---- Drawing validation protocols,Execution of protocol(Cleaning of equipment as per SOP),selection of worst case scenario
QA Department:- Co-ordinating the selection of worst case scenario,analytical support(sampling,testing),documentation of results Co-ordinating the selection of worst case scenario,analytical support(sampling,testing),documentation of results, Approval of validation protocols
5. Products covered under the exercise:
The following is a List of Products manufactured in the facility/equipment covered by this exercise:

Give List
6. Equipment List:
Following is a list of the Equipments covered under this exercise:
GIVE TABLE----(See sample Document at the end of this post).
The relevant shadings to be given for each product manufacture along with key at the end of the table

7. Cleaning Procedure:The following common cleaning procedure has been rationalized for cleaning the equipment:
a)Clean the surface of the vessel using jets of D/M water
b)Wash with hot water followed by D/M water wash
Give steps in brief

This cleaning validation exercise includes the product contact equipment viz.-------eg solutioning tanks,holding tanks,filling pumps-----

This cleaning validation exercise does not include non-product contact equipment eg external surfaces of closed syd\stems,peristaltic pumps,waste systems-------

Prior to commencement of this exercise,all existing cleaning procedures have been reviewed to ensure that the procedure is well defined,reproducible and can be validated. It is also made clear whether any different treatment is needed for a particular product/s.Every cleaning procedure was reviewed for parameter such as unambiguous definition of cleaning location & equipment,instructions to disassemble & reassemble,ancilliary item cleaning,concentration of cleaning agent,no. of consecutive lots mfd without cleaning,maximim time between equipment use & cleaning,definition of Key parameters such as water quality,temperature,duration,Temperature,no of rinse cycles(Min & Max),Drying(if required)etc

The references of the relevant SOPs are already addressed in Table ----(above)

8. Validation Approach:The matrix approach has bbeen chosen since the same cleaning procedure is followed for all the equipment and area irrespective of the product manufactured in the facility.
The worst case contaminant,recepient and equipment have been chosen to validate the cleaning procedure.The straightforward approach ie to validate each piece of equipment for each product mfd is impractical since a large number of products are involved.The matrix approach allows the validation source to be focused on the more critical products.

9. Identification of the Marker Compound:
The marker identification matrix is prepared to identify the marker compound

The product which is least soluble,most toxic and having affinity for the equipment materials will be chosen as the marker compound.More than one can be chosen

If detergent or cleaning agent is used,residue studies shoul be conducted and should be used as an additional marker substance.

10. Selection of Worst Case-Justification-Worst case contaminant(active)-----give name ---Because it is slightly soluble in water
-Worst case recipient product---------Because of its lowest batch size
Worst case Equipment----------Mfg vessel,filling pump(FBD bags are product dedicated(for tabs) hence such parts are not critical while validating a cleaning procedure and acceptance criteria for such parts will be “ visually clean,dry & colourless”

11. Sampling Methods:The following methods have been used:
a)Visual inspection
b)Direct Surface Swabbing
c)Rinse solution analysis

The first one is a must. Either b or c can be chosen,but swabs are preferred

As it is impractical to swab 100 % of the mfg equipment or area, Sampling points were defined and are are given in the diagram below.

Diagram to be given

12. Determination of Total common equipment surface area coming in contact with the product:
Each equipment item was measured and complicated equipment were arithmetically broken down to basic geometric shapes to arrive at the calculations.
13. Cleanoing Process variables:
A)Cleaning agent temperature:It is generaaly assumed that the cleaning process will be improve d by increasing the water temp to promote solubilisation of the material.The worst case has been validated where water below the minimum stated temp has been used
B)Wash Rinse Duration & Volume/Flow rates:A longer duration as well as a faster flow rate increases the likelihood that the residual contaminant is removed.Hence the Wash Rinse Duration & Volume/Flow rates which are below the procedural rates have been studied.
c)Number of Wash/Rinse cycles:One less rinse has been given from the procedural norm during the validation runs.

D)Time between use & cleaning:Cleaning procedures stipulate the maximum delay allowable between use of equipment & cleaning.A worst case where the delay was more than the stipulated time has been carried out.
E0Cleaning only after campaigns:In the cleanong procedure the max no. of batches comprising a campaign & maximum delay allowable comprising a campaign & cleaning operations is defined.The cleaning validation will be done after 3 consecutive campaigns each with a diff no pf batcxhes and time periods.
f)Operator efficiency:The consistency of cleaning between two cleaning operators has been addressed.The operators have been traine din the cleaning operations and records are maintained in----------

14. Analytical Test Methods:The Analytical Test Methods have been validated and are detailed in --------.The efficiency of the sampling method has also been included in the method validation.The swabbing technique has been validated for :-the most effective solvent for each marker compound
-the percentage of product residue the swabbing procedure recovers from each equipment from the material under test
-the swab storage conditions and the time limit between sampling & testing
The recommended swab test area is 100 sq cm.

15. Limits and Acceptance criteria:
A)No more than 10 ppm of any product will appear in another product.
(Example of calculn:
10 ppm is equivalent to 10 mg in 1 kg
500 mg of compd x in 50 kg of compd y
The acceptance criteria will be No more than 500 mg of compd X will appear in a 50 kg batch of Product C)
B)No more than1/1000 (0.1%)of the std daily dose of the contaminant sh appear in the std daily dose of the following product
Eg-1/1000 of compd x,say 1/1000 of 5 mg=5mcg
Std daily doe of Product C(recepient)=2 mg
Acceptance criteria: No more than 5 mcg of compd X sh appear in 2 mg of Product C

16. Cleaning Validation Review:This will be done once every three years to confirm that the cleaning operation remains in a validated state
17. Cleaning Revalidation:Revalidation to requalify the cleaning process will be done which could be brought about by major changes or failures identified during cleaning validation moinitoring.

Hope you enjoy reading my posts on who gmp guideline for pharmaceuticals industry and pharma companies  .
you can see a sample document how it is prepared below.


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