Worst case identification for cleaning validation

Worst case identification for cleaning validation

• OBJECTIVE:

Objective of this SOP is to provide the procedure to be followed during worst case identification for cleaning validation. It also includes updating of API solubility – potency matrix, calculation of acceptable residue levels during cleaning validation.

• SCOPE:

This SOP covers the worst case selection criteria for validation of cleaning procedure for equipment used for Pharmaceutical  product manufacturing.

• RESPONSIBILITY :

Head QA will 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:

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

• ATTACHMENTS :

Template for “Worst case identification report for cleaning validation”                               – Attachment – I

• PROCEDURE:

6.1               During planning phase for execution of following activities, as a prerequisite, R & D / Production to provide BMR to QA team.

Worst case identification report for cleaning validation shall be prepared in the following cases.

• Introduction of new product
• Change in batch size of existing product
• Change in equipment train of existing product
• Change in the cleaning procedure

6.2               QA personnel shall check the completeness of BMR and prepare / update the following matrices to determine the new worst case and calculate MAC value.

• Solubility and potency matrix
• Maximum allowable carryover (MAC) calculation matrix

6.2.1      Solubility and potency matrix

• QA personnel shall check the availability for the solubility and potency matrix for each critical equipment specified under
• QA personnel shall prepare the solubility and potency matrix by following the below procedure:

6.2.1.1        The solubility and potency matrix shall include equipment name, provision to mention solubility and potency class, potency calculation formula and provision to enter identified worst case molecule as per solubility and potency.

6.2.1.2        Prepare a tabular matrix in which the provision to classify the APIs according to their solubility and potency classes shall be given. The solubility classes shall be based on the pharmacopoeia requirement.

 

Product category as per solubility	Product solubility in water
Very soluble	1 gm in less than 1 ml
Freely soluble	1 g min 1 to 10 ml
Soluble	1 gm in 10 to 30 ml
Sparingly soluble	1 gm in 30 to 100 ml
Slightly soluble	1 gm in 100 to 1000 ml
Very slightly soluble	1 gm in 1000 to 10000 ml
Insoluble	1 gm in more than 10000 ml

6.2.1.3        Сheck the API solubility in water and also calculate the potency of the product as per the below mentioned  formula.

Potency of product = Minimum effective concentration of the product 1000 (Safety factor)

6.2.1.4   In the matrix, enter the molecule in the respective class of solubility and potency.

6.2.1.5   An example for updating of Glimepiride in the solubility and potency matrix of an equipment is given below

Glimepiride is insoluble in water (Solubility in water = 1 gm in more than 10000 ml) and having minimum effective concentration as 1 mg (Potency = 0.001). So this product will be fitted in the matrix as follows.

6.2.1.6        QA personnel shall update the product in ‘Solubility and Potency matrix’ of each equipment from the equipment train using the procedure mentioned above.

Using this matrix, QA personnel shall compare the new product with the existing worst product to identify new worst case product for cleaning.

6.2.2  Maximum allowable carryover (MAC) calculation matrix :

QA personnel shall follow the below procedure to prepare and update the product in MAC calculation sheet. MAC calculation involves two parts.

6.2.2.1   Common surface area calculation sheet:

This excel spreadsheet calculates the common surface area for equipment train of new product with respect to existing product. During this calculation the product under assessment (i.e. new product) will be considered as “previous product” and “next product”.

For new product or equipment entry in the common surface area calculation sheet, QA personnel shall follow the following procedure:

• Enter the equipment name of newly introduced equipment in “equipment name” column. (Refer Figure I)
• Enter the product contact surface area of respective equipment (Both in “m2” and in “cm2”) in the column provided. (Refer Figure I)
• Enter product name in the respective column and row provided in the matrix (Refer Figure I- represents as a previous and the next product for the calculation of common equipment surface area).
• In product column, enter ‘1’ in front of the equipment intended to be use for manufacturing of respective product. (Refer Figure I).
• As per the formula, the excel spreadsheet shall determine the total product contact surface area of the equipment. (Refer Figure I).
• As per the formula, the excel spreadsheet shall determine the common equipment surface area between the products.

6.2.2.2   Acceptance criteria calculation sheet:

This is an equipment specific excel spreadsheet which determines the maximum allowable carryover (MAC) of the product as per 10 ppm and dose criteria. This validated sheet contains other product specific information like minimum effective dose, solubility, potency, LD₅₀ value, colour, batch size (in Kg and Units), maximum daily dose and lowest observed acceptance limit.

To enter a new product in the acceptance criteria calculation sheet, QA personnel shall follow the following procedure.

• Enter the equipment name of newly introduced product in the column of previous product and row of next product. (Refer Figure II).
• Enter the product information such as MED (mg), solubility in water, potency, LD₅₀ value (mg/kg) and colour of formulation in excel spreadsheet.
• Enter the details of batch size (both in kg and units) in the excel row provided below the previous product name (Refer Figure II).
• Enter the details of maximum daily dose (units) in the excel row provided below the batch size row (Refer Figure II).
• The common surface area required for the calculation will be automatically picked up from surface area calculation sheet. (Refer Figure II)
• The calculation of dose criteria will be done by the formula feed in the excel sheet and values will be displayed in terms of μg/100 cm² of swab (Refer Figure-II).
• The calculation of 10 ppm criteria will be done by the formula feed in the excel sheet and values will be displayed in terms of μg/100 cm² of swab (Refer Figure-II)
• The bottom row of excel spreadsheet shall determine the lowest value of maximum allowable carryover of existing products (if considered as a previous product) into the newly entered product (if considered as a next product), as shown in Figure-II.
• The right end column of excel spreadsheet shall determine the lowest value of maximum allowable carryover of newly entered product (if considered as a previous product) into the existing products (if considered as a next product), as shown in Figure-II.
• The right end corner of the excel spread sheet shall determine the lowest MAC value determined from all the MAC values throughout the excel spread sheet (Refer Figure II).The product which having lowest MAC value will be the worst case product with respect to the MAC value.
• Enter the stringent MAC value determined from all the MAC values throughout the excel spreadsheet and the respective combination of previous and next product.

MAC value to be calculated by following the procedure mentioned under step ‘B’

6.3          Worst case identification :

After matrix preparation and updation, QA personnel shall identify the new worst case by preparing the product specific ‘Worst case identification report for cleaning validation’ as per the annexure-I. QA personnel shall follow the below procedure for preparation of ‘Worst case identification report for cleaning validation’.

6.3.1      The ‘Worst case identification report for cleaning validation’ shall be numbered as WIR/KS/QA/XXX,

Where,

WIR stands for ‘Worst case identification report’

KS stands for Kusumpharm Sumy

QA stands for Quality assurance

XXX stands for serial number from 001 to 999.

6.3.2      Following parameters shall be considered during identification of worst case for cleaning validation:

6.3.2.1   Solubility of the APIs in water

If the product under assessment has less solubility compared to the existing validated worst case product on the equipment then the product under assessment shall be considered as new worst case for cleaning of the respective equipment.

Perform this activity for each equipment of the product equipment train under assessment.

If the product under assessment is not a new worst case (with respect to solubility) compared to the existing validated worst case product then the reference of existing worst case product and its related document references to be entered in the ‘Worst case identification report for cleaning validation’.

6.3.2.2   Potency of product:

If the product under assessment is having lowest value of potency (Lowest product strength/1000) compared to the existing validated worst case product on the equipment then the product under assessment shall be considered as a new worst case for cleaning validation of the respective equipment.

The product shall be classified as highly potent (products having strength< 1mg) and less potent (products having strength > 1mg).

Perform this activity for each equipment of the product equipment train under assessment.

If the product under assessment is not a new worst case (with respect to potency) compared to the existing validated worst case product then the reference of existing worst case product and its related document references is to be entered in the ‘Worst case identification report for cleaning validation’.

6.3.2.3   Maximum allowable carryover :

• To compare the MAC value of product under assessment with MAC value of existing worst case product, QA personnel shall refer the MAC value determination sheet.
• The stringent MAC value of the product under assessment for comparison will be the lowest MAC value calculated by considering new product as a previous and as a next product.
• If the MAC value of product under assessment is less than the MAC value of existing validated worst case product then the requirement of cleaning revalidation for worst case product is to be assessed for the revised limits. (For this assessment, cleaning validation results of existing validated worst case product are to be reviewed against new MAC value).
• As per the assessment, if the product under assessment is not a new worst case with respect to the MAC value but it is worst with respect to the solubility and/or potency then the cleaning validation is to be recommended to perform by applying the MAC value of worst case product.
• If the product under assessment is not a new worst case (with respect to MAC value) compared to the existing validated worst case product then the reference of existing worst case product and its related document references is to be entered in the ‘Worst case identification report for cleaning validation’.

6.3.2.4   Toxicity:

During the solubility potency assessment, if two products under assessment are having same potency and same solubility, then in this case that product which will be having the lowest LD50 value will be considered as worst case product.

6.3.2.5   Drug concentration:

When solubility of API for the product under cleaning validation assessment matches with the existing worst case product, in addition to solubility of API, batch size and drug concentration in the formulation shall be considered.

% drug concentration of the product under assessment shall be determined by using following formula,

% drug concentration = Label claim / Average weight x 100

6.3.2.6   Colour of formulation:

If the product under assessment contains the colour which is more difficult to remove (For e.g. water insoluble coating solution, coloured API etc.) compared to the colour used in the existing validated worst case product then product under assessment is to be recommended for cleaning validation by applying the MAC value of worst case product.

6.3.3            The worst case assessment for new product or new equipment for requirement of microbial assessment, CEHT, DEHT & Campaign length study is to be done by comparing with the existing validated worst case/

Following are the parameters to be considered for identification of new worst case during microbial   assessment, CEHT, DEHT & Campaign length study.

1. Nature of the product:

• Product which is hygroscopic and / or contains excipients which are prone to microbial growth. (Starch, Gelatine, Sucrose, Pre-gel starch, Calcium carbonate, Lactose, Talc, Sodium starch glycolate etc/)
• Product history

1. Manufacturing Process

• Manufacturing process which involves aqueous granulation
• Process / process parameters, where there is possibility for increase in microbial load (for e.g. banding, manual sieving, etc.)

1. Equipment design and construction

• Equipment with large product contact surfaces/Difficult to clean equipment/Equipment surfaces

• REFERENCES :

Validation master plan – QA/VMP /001

• ABBREVIATIONS :

MED: Minimum effective dose

CEHT: Cleaned equipment hold time study

DEHT: Dirty equipment hold time study

SOP: Standard operating procedure

GMP: Good manufacturing practices

gm: Gram

ppm: Part per million

Kg: Kilogram

ml:Milliliter

QC: Quality control

QA: Quality assurance

API: Active pharmaceutical ingredient

MAC: Maximum allowable carryover

LD50: It is the amount of material, which causes the death of 50% group test animals/

• DISTRIBUTUON LIST :

Quality assurance department

Quality control department

Production

10.0        HISTORY OF REVISION:

Version Number	Effective Date	Reason for Revision
		New SOP

 

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