Cleaning Validation Protocol

Cleaning Validation Protocol



1.0 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 of cleaning agents as well as the control of potential microbial contaminants.



The Cleaning Validation is not only ensuring 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.



2.0 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 routine phase, and to ensure that there is no 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) has 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.



3.0 Scope:

i. 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.



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



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



4.0 Responsibility:



i. QA/ QC Manager

ii. Validation Team Leader

iii. Validation Officer.

iv. Representative of Production Department.

v. Analyst

vi. Microbiologist



5.0 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.



6.0 Change Control:

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



i. Changing in Machine

ii. Change in cleaning agents used (if applicable)

iii. 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. _________________).



After the approval of any change according to procedure, it is required to revalidate the Cleaning Procedure.



7.0 Acceptance Criteria:





S. #


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 10 ppm of any product to appear in the next product.

c) For certain allergic ingredients, penicillines 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



8.0 Sampling Procedure:



Direct Surface 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 diluent. The tube is then agitated to suspend any viable microorganisms and aliquots are placed in a semisolid medium to obtain quantitative results.

9.0 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

10.0 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 5 ml 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 x 2 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.





11.0 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 Microbiologist takes the Swab Sample for Microbiological Determination.



iv. Send the Samples 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 results 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 results 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.



12.0 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 components:

· 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 components:
· 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 components: ______

· 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: ______



13.0 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 _________ Production 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 Operating/ Cleaning Procedure (SOP)




Analytical Result Sheet






13.4 Other Information: (if any)

Sampling procedure for purified water

Sampling procedure for purified water

OBJECTIVE:

To provide a procedure for sampling of purified water samples for chemical analysis.

SCOPE:

It applies to purified water from return loop and all points of use.

RESPONSIBILITY:

Chemist / Officer.

PROCEDURE:

Sampling :

Collect the purified water separately from return loop for complete chemical analysis and
from two points of use in rotation for performing only TOC and conductivity tests. For point
of use and its location refer Annexure – I and for sampling plan refer Annexure – II.

Initially flush approximate 1 liter of purified water from each point of use and return loop.

For chemical analysis, collect the purified water in 1000 ml screw cap bottle. Remove the cap of the bottle and rinse with the same purified water prior to sampling. Fill the bottle up to the shoulder so as to collect approximately 900 ml of purified water.

For TOC analysis, collect the purified water in 100 ml glass stoppered flask dedicated for it.
Remove the stopper of the flask and rinse with the sample to be collected prior to
sampling. Immediately stopper the flask after sampling of the purified water, to avoid

contamination of atmospheric carbon in sampled purified water.
Bring all collected purified water samples to Q.C. laboratory for testing.

SOP OF SOP

SOP of SOP (SOP on SOP) in Pharmaceuticals

1.0              OBJECTIVE

To
lay down a procedure for the preparation, approval, authorization, control and
revision of Standard Operating Procedures.

 

2.0              SCOPE

This
SOP describes the basic principles, defines the responsibilities and lays down
the procedure for preparing SOPs. This SOP shall be applicable to all the SOPs
at ................

3.0              RESPONSIBILITY

3.1       Preparation &
Execution: Executive and above

3.2       Approval: Asst. Manager
and above

3.3       Authorization: Asst.
General Manager and above

 

4.0              ACCOUNTABILITY

Head
of the Concerned Department

 

5.0              PROCEDURE

 

 

5.1              Prepare the SOP on the approved
format on A-4 size paper.

 

5.2              Prepare the SOPs to
describe the operating procedures and steps.

 

5.3              Write all the SOPs in
clear, unambiguous language, easy to understand and easy to follow.

 

5.4              Write the SOPs under the
following sub-headings:

 

 

1.0          OBJECTIVE

2.0          SCOPE

3.0          RESPONSIBILITY

4.0          ACCOUNTABILITY

5.0          PROCEDURE

6.0          REFERENCES

7.0          ANNEXURES

8.0          ABBREVIATIONS

 

 

5.4.1                    OBJECTIVE

Write here the reason for preparing the SOP in one sentence or
maximum two sentences starting with a letter ‘To’.

 

5.4.2                    SCOPE

This Section defines the applicability of the SOP and also
specifies departments, areas or sections to which this SOP shall be applicable.

 

5.4.3                    RESPONSIBILITY

Write here the designation of the person / persons who are
directly responsible for the operations mentioned in the ‘Objective’ of the SOP.

 

5.4.4                    ACCOUNTABILITY

Write here the Head of the Department who is accountable for
compliance of the SOP.

 

5.4.5                    PROCEDURE

     
5.4.5.1   Write the procedure/method in short sentences. Do not write
the instructions in long paragraphs.

 

5.4.5.2   
 Mention all the checks to be carried out, records to be maintained,
frequency of various operations, checks and special precautions, if any.

5.4.5.4       Enclose all the
Annexures with SOP if applicable.

 

5.4.6                    REFERENCES

Mention
a list of references or any other guidance documents based on which the SOP has
been prepared. If there is no reference for the SOP, mention ‘Not Applicable’
under this subheading.

 

5.4.7                    ANNEXURES

                 
Mention a list of all Annexures enclosed in the SOP. If there is no Annexure in
the SOP, mention ‘Not Applicable’ under this subheading.

 

 

5.4.8        ABBREVIATIONS :

Mention
a list of all abbreviations & their full forms/descriptions used in the
SOP. If there is no Abbreviation in the SOP, mention ‘Not Applicable’ under
this subheading.

 

 

5.5                 Write the SOP in English
(If required, some of the SOPs shall be written in local language i.e Hindi).

 

5.6                 FORMAT
REQUIREMENTS :

Prepare all the SOPs as per specimen format given as Annexure I
to this SOP.

The
type of font for the contents in SOPs shall be  ‘Times New Roman’ .The font size to be used
for contents of SOPs shall be as follows:

 

5.6.1           FONTS

 

 

Content of SOP	Size of Font
Header
“STANDARD OPERATING PROCEDURE” & “TITLE”	12 Bold in Upper Case
Torrent Logo on the right hand corner	30 mm (L) x 6 mm(H)
“TORRENT” ( on top left corner )	14 Bold in Upper Case
“Pharmaceutical Ltd.” “Restricted Circulation” “Location”, “Dept.”, “Area”, “Page”, “SOP No.”, “Revision No.” “Effective Date”, “Supersedes”, “Review Date”, “Initiated By”, “Approved By”, “Authorized By”, “Name”, “Signature & Date”	10 Bold in Title Case
Actual Title ( detailed heading ) of SOP	12 Bold in Upper Case
Body
Subheadings	12 Bold in Upper Case
Write up of SOP	12 in Sentence Case
Footer
“Format No.”	10 in Title Case
Actual format number	10 in Upper Case

 

5.7              NUMBERING
SYSTEM OF  SOP

 

5.7.1      Each SOP
shall have a unique numbering system. Once number is allocated to any SOP, the
same   number shall not be repeated to other SOP.

 

5.7.2      Each SOP
No. consists of seven alphanumerical characters. For example first SOP prepared
in the QA department shall be numbered as BQA-001.

5.7.2.1  
1^st alpha character indicates the location code where ‘B’ indicates
for Baddi.

5.7.2.2      2^nd alpha character indicates department code and 3^rd alpha character indicates subsection/area code  for the
departments mentioned in the point no. 5.7.3.

5.7.2.3      For departments other
than point no. 5.7.3,  2^nd   & 3^rd alpha characters indicate department code as mentioned in the
point no. 5.7.4.

5.7.2.4      4^th character is dash’-‘ for separator.

5.7.2.5      5^th ,6^th & 7^th numerical characters
indicate serial number of that particular department code. ‘001’ indicates
first SOP prepared under particular department code.

 

5.7.3            Department wise Code for
SOP Numbering system for Manufacturing and Quality Control:

 

Department	Department Code	General	Operational & Calibration	Cleaning	Code for SOP No.
Beta Lactam
Mfg. & Packing	B	G	O	C	BG/BO/BC
Non Beta Lactam
Capsules	C	G	O	C	CG/CO/CC
Liquid Orals	L	G	O	C	LG/LO/LC
Packing	P	G	O	C	PG/PO/PC
Quality Control	Q	G	O	C	QG/QO/QC
Tablets	T	G	O	C	TG/TO/TC
Other Departments
Engineering	E	G	O	C	EG/EO/EC
Safety, Health & Environment	S	G	O	C	SG/SO/SC
Ware House ( RM, PM, FG Quarantine )	W	G	O	C	WG/WO/WC

 

5.7.4              Department wise Code for
SOP Numbering system for other departments:

 

Department	Code for SOP No.
Accounts	AC
Administration	AD
Human Resources & Development	HR
Information Technology	IT
Production Planning & Supply Chain	PP
Purchase	PU
Quality Assurance	QA

 

5.7.5              For example, the first
General SOP of Tablet department shall be numbered as BTG-001.

 

  
5.8        CONTENTS OF HEADER

  

5.8.1              Location : The name of location of the plant  for which SOP is
applicable.

5.8.2              Department : The name of the Department for which SOP is applicable.

5.8.3              Area: The area / sub-section of the Department shall be mentioned
wherever applicable.

5.8.4              Title: Detailed heading of the SOP.

5.8.5              SOP No.: Unique SOP No. as per procedures described in the point no. 5.7
shall be mentioned here.

5.8.6              Revision No. :  Revision No. consists of two numerical characters which
start from ‘00’ with increment in one digit after each revision. ‘00’ indicates
the first issuance of that particular SOP.

5.8.7              Effective Date: The effective date shall be stamped by Q.A. after final
authorization before circulating the SOPs.

5.8.8              Supersedes: For the first issuance, ‘New introduction’ shall be mentioned in
this column, otherwise  effective date of obsolete ( previous) SOP shall
be mentioned.

5.8.9              Review Date: The normal review period will be 2 years from the effective date
of the SOP. For example if any SOP is having effective date “07-10-2004”, its
review date will be “07-10-2006”. Revision of SOPs shall be done as per
procedure mentioned in the point no. 5.13.

5.8.10          Page : The  page number shall be mentioned in ‘xx of yy’ format.

5.8.11          Signatures : The Header comprises of three columns i.e. Initiated By,
Approved By & Authorized by.

              
Each of the three columns consist of 3 rows i.e. Name of the person who signs
the SOP in full signature and the date on which the person signs the SOP.

5.8.11.1    Initiated by : Designated person, who has initiated  the SOP shall
write  name clearly  with  signature &  date in blue
ink in the column “Initiated By”. 

5.8.11.2    Approved by: Two persons shall approve the SOP after review. One of them
shall be concerned Department Head and the other shall be Head of Quality
Assurance. They shall write name clearly with signature and date in blue ink.
In case of QA SOPs first approval shall be done by Asst. Manager and above and
second approval shall be done by the Manager and above of the  Quality
Assurance Department.

5.8.11.3    Authorized by: The person finally authorizing the SOP, shall sign here.
Authorization shall be done by Location Head, who shall write name clearly with
signature and date in blue ink. In case of QA SOPs, the Location QA Head shall
authorize all the SOPs except the SOP No. BQA-001 (Preparation, Approval,
Authorization, Control and Revision of SOPs). This SOP shall be authorized by
Vice President – Corporate QA.

 

5.9     
   CONTENTS OF FOOTER

 

5.9.1       Format No.: This is a unique number assigned to the format used for
preparation of all SOPs as described in the point no. 5.11.4.

 

5.10                GENERATION OF NEW
SOPs

 

5.10.1          User dept. shall prepare
the draft SOP as per the procedure described in the point no.5.4 to 5.9. Draft
copy shall be identified by stamping or water mark on each page.

 

5.10.2          Draft copy shall be
circulated to the responsible persons for its review. The responsible persons
may recommend  for any changes in the text.

 

5.10.3          Based on the
recommendation, user dept. shall correct the draft SOP and take final print out
for approval and authorization along with Change History Log.

 

5.10.4          After approval and
authorization, user dept. shall submit the Original Copy ( Master Copy ) of SOP
along with ‘Change History Log’ to QA for control and issuance and shall
destroy the draft SOP.