CLEANING VALIDATION PROTOCOL FOR PHARMACEUTICALS

1.      Introduction:

The validation of the cleaning procedures is establishing documented evidence that the procedure is effective and capable for removing the contaminants associated with previous products, residues agents as well as the control of potential microbial contaminants.

The cleaning validation is not only ensure the compliance of the regulatory requirements, but a more important benefit for performing cleaning procedure validation is the identification and the correction of the potential problems which could compromise the safety, efficacy or quality of the subsequent batches of drug product.

2.      Objective:

The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients and/or cleaning agents so that the analytical monitoring may be reduced to a minimum in the risk associated with cross-contamination of active ingredients.

The objective of Validation of the cleaning procedure (SOP No :___________) being used for the cleaning of machine name (Machine No :___________) is to prove that the product contact parts of the Machine name (Machine No :__________) have been cleaned and that the contamination level (Chemical and Microbial Contaminants) had been reduced below to an acceptable level.

To achieve these acceptable levels, cleaning procedure (SOP No :___________) need to be established and validated; sampling and analysis will be carried out for this purpose to assure that the cleaning of machine complies with specified limits.

Cleaning validation will verify the effectiveness of cleaning procedure.

3.      Scope:

a)    This document on cleaning validation is intended to address special consideration and issues pertaining to validation of cleaning procedure (SOP No :____________) of Machine Name (Machine No :___________) used for tablets Compression of Pharmaceutical products.

b)   This document is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures.

c)    This document is intended to cover validation of equipment cleaning for removal of contaminants associated to the previous product, residues of cleaning agents as well as the control of potential microbial contaminants.

4.      Responsibility:

            a)      QA/QC Manager

            b)      Validation Team Leader

            c)      Validation officer

            d)     Representative of Production Department.

            e)      Analyst

            f)       Microbiologist

5.      Validation Program:

Equipment cleaning validation may be performed concurrently with actual production steps during process development and bulk manufacturing. Validation programs should be continued through full scale commercial production.

The concept “Test-Until-Clean” will be applied. This concept involves cleaning, sampling and testing with repetition of this sequence until an acceptable residue limit is attained.

A validation program generally encompasses at least three consecutive successful replicate to establish that the procedure is reproducibly effective.

If the equipment of the similar size, design and construction is cleaned by the same procedure, studies need not to be conducted on each unit as long as a total of three successful replicates are done on similar piece of equipment; this concept is known as equipment grouping.

6.      Change Control:

Any of the following proposed changes are evaluated fully for their impact on the validated state of the procedure. Changes may be,

a)     Changing in Machine

b)    Change in cleaning agents used (if applicable)

c)     Change in cleaning procedures

If any of the above-cited changes are required it should be performed in accordance with the change control procedure (SOP No :____________).

7.      Acceptance Criteria:

S.No	Testing Parameter	Acceptance Criteria
1	Physical Determination	The visual examination of the equipment verifying that visible residues or Particulate matters.
2	Chemical Determination	a) NMT 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the subsequent product.
		b) NMT 10ppm of any product to appear in the next product.
		c) For certain allergic ingredients, penicillin’s cephalosporin of steroids and cytotoxic, the limit should be below the limit of detection.
3	Microbial Contamination	Total aerobic Counts
		a) Bacterial Counts = NMT 20 CFU
		b) Molds = NMT 02 CFU

8.      Sampling Procedure:

Direct sampling (Swab Method):

a)      Area difficult to clean and which are reasonably clean can be evaluated by direct surface sampling method (Swab Method), leading to establish a level of contamination or residue per given area i.e. 60-100 in2. The residue that are dried out or are insoluble can be sampled by swab Method.

b)      The suitability of the method to be used for sampling and of sampling medium should be determined. The ability to recover the sample accurately may be affected by the choice of sampling method. It is important to assure the sampling medium and solvent (Used for extraction from the medium) are satisfactory and can be readily used.

c)      For determination of the microbiological contamination on surfaces is to use sterile cotton swabs moistened with sterile peptone water, WFI, or Phosphate Buffer. Using sterile forceps and aseptic technique, an area of predetermined size, e.g. 60-100 in2, is wiped with a sterile swab. The swab is then aseptically transferred to a sterile tube containing a suitable diluents. The tube is then agitated to suspend any viable microorganisms and aliquots are placed in a semisolid medium to obtain quantitative results.

9.      Cleaning Procedure: SOP No.______________

                    i.            Switch off the Machine

                  ii.            Write down complete cleaning procedure step wise

                iii.            After cleaning paste cleaning status label and enter in logbook

10.  Testing Procedure:

                    i.            Physical testing:

Along with taking samples, it is important to perform visual inspection as well to ensure the process acceptability.

                  ii.            Chemical Testing:

Write down the analytical procedure for determination of traces at least three active pharmaceutical ingredients.

                iii.            Microbiological Testing:

Swab test

·         Cotton swabs prepared on S.S sticks are sterilized.

·         Phosphate buffer pH 7.2 prepared and dispensed 5ml in each screw capped test tubes is sterilized.

·         Material is transferred into sterile area for swab test after disinfection.

·         Remove the sterilized swab, soak in phosphate buffer and touch to the surface to be checked.

·         2 ½ X2 ½ inch² area is touched against each soaked swab.

·         Place back the swab into the tube containing phosphate buffer and label the tube with the testing part and date.

·         Transfer the tested swab to micro lab. For microbiological test.

·         Pour plate method is used to check the contaminants.

·         Plates are incubated for 48 hours, the results are declared as number of CFU per part or surface.

11.  Overall Validation Procedure:

                    i.            Intimate the Production Department for the cleaning validation of Machine name (Machine No.______________) before starting the activity through cleaning Validation Schedule.

                  ii.            After Cleaning of the Machine name (Machine No._____________) according to procedure (SOP No._____________) Production Department inform the validation section for conducting the Validation activities.

                iii.            Validation Officer takes the swab sample for chemical determination, whereas microbiological Determination.

                iv.            Send the sample to quality control along with Technical information sheet for analysis.

                  v.            QCD analyzes the sample according to procedure and provide the results to validation section.

                vi.            Repeat the steps ii, iii, and iv after the change of consecutive three different products.

              vii.            Validation section analyzes all the results and compiles the report.

            viii.            If the result comply with the specified limits than the machine name (Machine No.______________) is considered as cleaned and the cleaning procedure (SOP No.______________) is considered as validated.

                ix.            If the result do not comply with the specified limits, then repeat the overall validation actives for further two consecutive changes of different products i.e. to provide the validation data of three consecutive API’s.

                  x.            If the validation results do not comply with the specification, improve the cleaning procedure and continue it until all the results comply with the specified limits.

12.  Inspection Criteria: (For three consecutive products)

12.1

Previous Product	Batch No
While taking samples from Machine Name (Machine No.______________). Note Down the following Points.
Description of Machine/Equipment/Area:__________________________
Major Product contact componints:_______________________________
Product contact area:__________________________________________
Previous Batch completed on:__________________________________
Equipment cleaned on:_________________________________________
Detergent/Solvent used:_________________________________________
Composition of the detergent used:________________________________
Cleaning Tools:_______________________________________________
Ancillary Utilities:_____________________________________________
Cleaning Cycles:______________________________________________
Cleaned By:___________________________________________________
Supervised By:_________________________________________________
Sampled By (Chemical):_________________________________________
Sampled By (Microbiological):____________________________________
After cleaning the Equipment used on:_______________________________
Subsequent Product:_______________________________________________
Batch No:________________________________________________________
Name of API:____________________________________________________
Batch Size of the subsequent Product:_________________________________
Maximum daily dose of the subsequent product:_________________________

12.2

Previous Product	Batch No
While taking samples from Machine Name (Machine No.______________). Note Down the following Points.
Description of Machine/Equipment/Area:___________________________
Major Product contact componints:________________________________
Product contact area:____________________________________________
Previous Batch completed on:_____________________________________
Equipment cleaned on:__________________________________________
Detergent/Solvent used:_________________________________________
Composition of the detergent used:_________________________________
Cleaning Tools:________________________________________________
Ancillary Utilities:______________________________________________
Cleaning Cycles:_______________________________________________
Cleaned By:___________________________________________________
Supervised By:_________________________________________________
Sampled By (Chemical):_________________________________________
Sampled By (Microbiological):____________________________________
After cleaning the Equipment used on:______________________________
Subsequent Product:____________________________________________
Batch No:____________________________________________________
Name of API:__________________________________________________
Batch Size of the subsequent Product:_______________________________
Maximum daily dose of the subsequent product:_______________________

12.3

Previous Product	Batch No
While taking samples from Machine Name (Machine No.______________). Note Down the following Points.
Description of Machine/Equipment/Area:_____________________________
Major Product contact componints:_________________________________
Product contact area:_____________________________________________
Previous Batch completed on:______________________________________
Equipment cleaned on:____________________________________________
Detergent/Solvent used:___________________________________________
Composition of the detergent used:__________________________________
Cleaning Tools:_________________________________________________
Ancillary Utilities:________________________________________________
Cleaning Cycles:_________________________________________________
Cleaned By:_____________________________________________________
Supervised By:___________________________________________________
Sampled By (Chemical):____________________________________________
Sampled By (Microbiological):_______________________________________
After cleaning the Equipment used on:________________________________
Subsequent Product:_______________________________________________
Batch No:________________________________________________________
Name of API:____________________________________________________
Batch Size of the subsequent Product:_________________________________
Maximum daily dose of the subsequent product:________________________

13.  Facilities/Responsible Personnel & Documentation:

13.1 Facilities:

The validation of cleaning procedure being used for the cleaning of Machine Name (Machine No.___________) was performed in ______________ section of ___________Product at company Name and address.

13.2 Identification of Responsible Personnel:

Name	Job Title	Signature

13.3 Identification of Documentation:

Document Title	SOP/QF Number
Validation Master Plan
Cleaning Validation (SOP)
Cleaning Validation Report
Machine Opetating/ Cleaning Procedur (SOP)
Analytical Result Sheet

13.4 Other Information (if any):