Cleaning validation in pharmaceuticals

Pharmaceutical Guidanace July 19, 2019 QA & QC, Quality Assurance Comments Off on Cleaning validation in pharmaceuticals 9,785 Views

Cleaning validation

OBJECTIVE :

Objective of this SOP is to provide the procedure to be followed during cleaning validation.

SCOPE :

This SOP covers the validation of cleaning procedure for equipment used for product manufacturing in pharm, company.

RESPONSIBILITY :

QA officer shall be responsible for issuing & implementation of this SOP.

It is the prime responsibility of all users of QA, Production & QC to follow this SOP.

ACCOUNTABILITY:

Quality Assurance Head, Quality Control Head, Production Head shall be accountable for compliance of the procedure mentioned in this SOP.

ATTACHMENTS / ПРИЛОЖЕНИЯ:

Template for comprehensive cleaning validation protocol – Attachment – I

Template for cleaning validation summary report – Attachment – II

Template for study specific cleaning validation protocol – Attachment – III

Template for study specific cleaning validation report – Attachment – IV

PROCEDURE :

6.1 Requirements:

6.1.1 An Approved cleaning procedure (SOP) shall be available for equipment under validation

6.1.2 Before proceeding for cleaning validation execution, the analytical and sampling method shall be available.

6.1.3 Cleaning validation protocol shall be prepared. The protocol shall outline the steps to be followed during execution of cleaning validation studies.

6.1.4 Critical equipment parts with respect to cleaning (i.e. product contact parts) for sampling shall be identified and documented before performing the validation.

6.1.5 Cleaning procedure to be validated with three consecutive runs of recommended worst case product to check the consistency for chemical and microbiological cleanliness. (For CEHT, DHET and campaign length study, one run of worst case product shall be considered for validation).

6.1.6 During cleaning validation, swab sampling method shall be used, however, rinsing methods can also be used when swabbing is impractical and the residues are soluble. For rinse water, sample to be collected from final wash of equipment.

6.1.7 Before execution of sampling activity, equipment shall be visually clean.

6.1.8 Definitions / Определения

Dirty Equipment Hold Time (DEHT): Elapsed time between the end of a manufacturing / packaging process аnd execution of the complete cleaning procedure.
Clean Equipment Hold Time (CEHT): Elapsed time between the end of a complete cleaning process and introduction of product for the next use.
Campaign length: Number of batches of same product and same strength processed between complete cleaning runs. During campaign manufacturing between two batches equipment and area to be cleaned as per general cleaning procedure.

6.2 Following are the steps to be followed for execution of cleaning validation programе.

Worst case identification for cleaning validation

6.2.1 Input for cleaning worst case identification

From BMR, QA personnel should collect details for assessment of worst case identification.

6.2.2 Preparation and / or updation of equipment based matrix :

QA personnel shall refer the details from BMR and prepare and/or update the equipment based matrix as per the current version of SOP/ QA/085 (Worst case identification for cleaning validation).

6.2.3 Preparation of ‘Worst case identification report for cleaning validation’:

To identify the new worst case and to determine the necessity of cleaning validation, QA personnel shall prepare the product based ‘Worst case identification report for cleaning validation’ as per SOP/QA/085. The ‘Worst case identification report for cleaning validation’ shall evaluate the potential risk and requirement for chemical cleanliness verification (i.e. API residues), microbial assessment, clean equipment hold time, dirty equipment hold time.

6.2.3.1 Chemical cleanliness:

The acceptance criteria for chemical cleanliness are as below

10 ppm Criteria:

This criteria is followed to determine the maximum allowable concentration of residual API

Maximum allowable carryover in mcg/100sq.cm as per 10 PPM criteria =

10 B. size of next product in Kg

= ————– x————————————– x100* x 1000# x 1000# x1000#

1,000,000 CSA (sq. cm)

Where

CSA – Common surface area

10/1000000- 10 ppm

100* – Factor used to convert the maximum allowable content per 100 sq.cm

1000# – Factor used to convert the maximum allowable content into ‘mcg’

Dose criteria:

Maximum allowable carryover (MAC) of previous product to next product is not more than 1/1000th of minimum dose of previous product in maximum daily dose of next product. Calculation of limit per swab as per this criteria is done as per the formula given below

Dose criteria=

Maximum allowable carryover in mcg/100 sq.cm as per dose criteria =

MEDpp (mg) X B. size of next product (units) X 100* X 1000#

= —————————————————————————————-

1000 X MDDnp (units) X CSA (sq. cm)

Where:

MEDpp – Minimum effective dose of previous product

MDDnp – Maximum daily dose of next product

CSA – Common surface area

1/1000 – Safety factor

100*- Factor used to convert the maximum allowable content per 100sq.cm

1000# – Factor used to convert the maximum allowable content into ‘mcg’

Permitted Daily Exposure Criteria:

Maximum allowable carryover (MAC) should be based upon the Permitted Daily Exposure. The principle of MAC calculation is that you calculate acceptable carryover for your previous product based upon the PDE into your next product. Calculation of limit per swab as per this criteria is done as per the formula given below

PDE x mBS X 100*

MAC = ———————————— ,

MDDnp (units) X CSA (sq. cm)

Where

PDE – Permitted daily exposure

mBS – minimum batch size

MDDnp – Maximum daily dose of next product

CSA – Common surface area

100*- Factor used to convert the maximum allowable content per 100sq.cm

Note: PDE based criteria shall be applicable for new products (new development) introduced at site.

Visual clean criteria: The limit as per this criteria is not more than 400 µg / 100. sq.cm

To arrive at the final acceptance limit using matrix approach, acceptance limit for swab shall be calculated for each permutation of product as previous & next product using above formulae. The most stringent limit out of the all the permutations shall be accepted as the limit
In case of active ingredient, the most stringent limit amongst 10 ppm, 1/1000th dose criteria and visual clean criteria will be used as the acceptance criteria
For dedicated equipment, cleaning validation shall be reduced to validate the cleaning procedure for the removal of microbiological assessment up to the predetermined acceptance criteria. The cleaning procedure must ensure that the equipment is visually clean

Note: On the basis of MAC calculation of all above mentioned criteria the minimum MAC value of the product shall be considered as a Worst Case Product.

6.2.3.2 Hygienic cleanliness:

The acceptance criteria for hygienic cleanliness are as below:

Acceptance criteria

Microbial assessment

Permissible number of total microbial count and mold per 100 cm² is 50 CFU and 10 CFU respectively

Clean equipment hold time (CEHT) assessment

Permissible number of total microbial count and mold per 100 cm² is 50 CFU and 10 CFU respectively

Dirty equipment hold time (DEHT) assessment

Cleaned equipment: Permissible number of total microbial count and mold per 100 cm² is 50 CFU and 10 CFU respectively

Campaign length

Uncleaned equipment: Permissible number of total microbial count and fungal per 100 cm² is 100 CFU and 20 CFU respectively.

Cleaned equipment: Permissible number of total microbial count and mold per 100 cm² is 50 CFU and 10 CFU respectively

Note:

In addition to above, QA personnel shall consider the following points during worst case identification

If the cleaning validation (Chemical cleanliness and hygienic cleanliness) with worst case product is successfully completed on a particular equipment then for other products on the same equipment cleaning validation is not required. (The assessment and the rational shall be documented in ‘Worst case identification report for cleaning validation’).
If the equipment identified for cleaning validation is available with various volumetric capacity and if the equipment with higher and lower capacity (With having same cleaning procedure) is already validated then no need to validate the other capacities of the same equipment (Equipment equivalency and impact assessment shall be documented).

6.3 Preparation of validation protocol :

6.3.1 QA personnel shall prepare the comprehensive cleaning validation protocol as per the Attachment-I of this SOP. The protocol shall describe about the general procedure to be followed to demonstrate the effectiveness of cleaning procedure to establish. Chemical cleanliness (i.e. no contamination with active residues and residues of cleaning agent). The protocol shall describe about the sampling method and selection of critical equipment parts for sampling.

6.3.2 For below mentioned studies, QA personnel shall prepare the study specific protocol as per Attachment-III. This protocol shall describe the detailed procedure to be followed during execution of respective studies

Hygienic cleanliness (no contamination with bacteria and fungi)
Cleaning intervals and idle times on dirty Equipment hold time (DEHT), Clean equipment hold time (CEHT) studies and Campaign length study.

The protocol shall describe about the sampling method and selection of critical equipment parts for Sampling.

6.3.3 Execution of cleaning validation :

If decision is made to perform the cleaning validation in accordance with the recommendations from ‘Worst case identification report for cleaning validation’, following procedure is to be followed to execute the validation activity:

QA personnel shall check the prerequisite as per the step 6.1.
As per the scheduled plan, production personnel shall clean the equipment by following the mentioned cleaning procedure.
After equipment cleaning, production personnel shall raise an “Analysis request cum report” to intimate IPQA for sampling.
Prior to sampling, sampler shall perform visual inspection of the cleaned equipment for the absence of particulate matter.
If the equipment is found visually clean then sampler shall follow the approved cleaning validation protocol, respective product specific sampling method.
As per the recommendations from ‘Worst case identification report for cleaning validation’, sampler shall collect the samples for chemical assessment and / or hygienic cleanliness following the respective sampling procedure and submit the samples to QC for analysis.

QC personnel shall perform the analysis as per the approved analytical and microbiological method and submit the results to QA group for compilation and preparation of cleaning validation report

6.3.4 For chemical cleanliness assessment and microbial assessment, repeat the procedure from step 6.3.3 for two more consecutive runs as a part of cleaning validation program

6.3.5 QC personnel shall check, if requirements for individual equipment meet the criteria of cleaning validation. In case of result failures, QA shall initiate an investigation with QC and production personnel for root cause analysis.

Note: In case of any change in the cleaning procedure required, a product specific cleaning procedure shall be prepared and validated.

6.4 Cleaning validation report :

6.4.1 QA personnel shall prepare equipment specific cleaning validation summary report for chemical cleanliness and hygienic cleanliness as per the Attachment-II.

6.4.2 Validation summary report shall contain the outcome of the validation exercise, conclusion and recommendations.

6.4.3 Based on the protocol of CEHT, DEHT assessment, Campaign length study and microbial assessment, QA personnel shall prepare a separate study specific report (refer Attachment-IV). The reference of these reports shall be given in the final summary report of respective equipment.

6.4.4 On successful completion of cleaning validation, the respective cleaning procedure can be considered as validated for the respective equipment.

6.5 Revalidation :

6.5.1 Revalidation due to change :

Requirement for revalidation is to be assessed during the following significant changes:

Change in equipment cleaning procedure.
If new product introduced in the plant which is new worst case on the equipment.
Change in cleaning agent.
Critical modifications in equipment which impacts effectiveness of existing cleaning procedure.

REFERENCES:

Validation master plan .

ABBREVIATIONS :

ppm: Parts per Million

SOP: Standard Operating Procedure

sq.cm.: Square Centimetre

CFU: Colony forming Units

mcg: Microgram

API: Active Pharmaceutical Ingredient

QA: Quality Assurance

IPQA: In process Quality Assurance

QC: Quality Control

CEHT: Clean equipment hold time

DEHT: Dirty equipment hold time

PDE: Permitted Daily Exposure

MAC: Maximum allowable carryover

DISTRIBUTUON LIST:

Quality Assurance department

Quality Control department

Production department

10.0 HISTORY OF REVISION :

Version Number

Effective Date

Reason for Revision

New SOP

Attachment- 1

CLEANING VALIDATION PROTOCOL FOR MANUFACTURING EQUIPMENT

Protocol No

Version

Title: Cleaned equipment hold time study/Dirty equipment hold time study/Microbial assessment report

Prepared By:

By signing, the person is responsible for the accuracy of this report and agrees with the content

Name

Department

Signature

Date

Prepared By

Reviewed By :

Reviewer should have expertise to critically assess the content and accuracy of the document.

The review and Acceptance by signing shall signify that the report is complete, technically

accurate and meets validation requirements.

	Name	Department	Signature	Date
Reviewed By		QA
Reviewed By		Production
Reviewed		Quality Control

Approver’s Signature:

The approvers confirms that this report is adequate.

	Name	Department	Signature	Date
Approvers By		QA Head

Table of Contents

Title
Report objective
Reference documents
Responsibilities
Acceptance criteria
Deviations /OOS (If Any)
Procedure
Review/comparison of results
Conclusion
Attachment/Annexure(s), if any
Reason for change

Attachment- II

cleaning validation summary report

Report No

Title: cleaning validation summary report

Prepared By:

By signing, the person is responsible for the accuracy of this report and agrees with the content

Name

Department

Signature

Date

Prepared By

Reviewed By :

Reviewer should have expertise to critically assess the content and accuracy of the document.

The review and Acceptance by signing shall signify that the report is complete, technically

accurate and meets validation requirements.

	Name	Department	Signature	Date
Reviewed By		QA
Reviewed By		Production
Reviewed		Quality Control

Approver’s Signature:

The approvers confirms that this report is adequate.

	Name	Department	Signature	Date
Approvers By		QA Head

Table of Contents

Title
Report objective
Reference documents
Description of tests to be carried out
Acceptance criteria
Deviations /OOS (If Any)
Review / Comparison of results
Final Summary and conclusion
Reason for change

Attachment- III

Cleaned equipment hold time study/Dirty equipment hold time study/Microbial assessment protocol/Periodic cleaning revalidation

Protocol No.

Title: Cleaned equipment hold time study/Dirty equipment hold time study/Microbial assessment protocol/Periodic cleaning re-validation

Prepared By:

By signing, the person is responsible for the accuracy of this report and agrees with the content

Name

Department

Signature

Date

Prepared By

Reviewed By :

Reviewer should have expertise to critically assess the content and accuracy of the document.

The review and Acceptance by signing shall signify that the report is complete, technically

accurate and meets validation requirements.

	Name	Department	Signature	Date
Reviewed By		QA
Reviewed By		Production
Reviewed		Quality Control

Approver’s Signature:

The approvers confirms that this report is adequate.

	Name	Department	Signature	Date
Approvers By		QA Head

Table of Contents

Objective
Scope
Responsibility
Reference(s)
Procedure
Acceptance criteria
Conclusion
Abbreviation(s)
Changes from last edition

Attachment- IV

Cleaned equipment hold time study/Dirty equipment hold time study/campaign length study / Microbial assessment REPORT

Protocol No.

Title:

Cleaned equipment hold time study/Dirty equipment hold time study/campaign length study / Microbial assessment REPORT

Prepared By:

By signing, the person is responsible for the accuracy of this report and agrees with the content

Name

Department

Signature

Date

Prepared By

Reviewed By :

Reviewer should have expertise to critically assess the content and accuracy of the document.

The review and Acceptance by signing shall signify that the report is complete, technically

accurate and meets validation requirements.

	Name	Department	Signature	Date
Reviewed By		QA
Reviewed By		Production
Reviewed		Quality Control

Approver’s Signature:

The approvers confirms that this report is adequate.

	Name	Department	Signature	Date
Approvers By		QA Head

Table of Contents

Title
Report objective
Reference documents
Responsibilities
Acceptance criteria
Deviations /OOS (If Any)
Procedure
Review/comparison of results
Conclusion
Attachment/Annexure(s), if any
Reason for change

Cleaning validation in pharmaceuticals