CLEANING VALIDATION

CLEANING VALIDATION

CLEANING VALIDATION

APPROACH , Part-1

Raktim Dey

DY. Manager (VALIDATIONS & QUALIFICATIONS), Granules India Limited

Why do we need to perform  Cleaning Validation?

  • In a multiproduct facility, it is not feasible to analyze each and every product changeover through chemical Swab/Rinse analysis.
  • Hence , Cleaning validation study is introduced to apply a worst case approach in selection of a particular molecule and then performing cleaning validation .
  • There is no terminology as “Absolute Clean” hence during Cleaning Validation, the carry over of the Previous Product is confirmed below an acceptable limit called MACO ( Maximum Allowable Carry over) into the subsequent product.

The FDA lists four criteria: (1) what can be reasonably achieved,

(2) what is medically safe, (3) what causes no product quality concerns, and

(4) what is visually clean.

Note: This presentation is part 1, as all aspects of Cleaning validation cannot be consolidated in one PPT.

Selection of Worst case Molecule for conducting Cleaning validation

Worst case molecules are selected basis to a Worst Case Rating of each molecule in a multi product facility. The following factors are considered while selecting a worst case molecule: a) Solubility

  1. Health Based Limit ( i.e. ADE/PDE value)
  2. Potency.

Emphasis shall also be given to molecule having Significant Colour, Flavor while determining worst case molecule.

Worst Case Rating of a Molecule:

The worst case rating of a molecule is given basis to it’s solubility, PDE value and Potency as follows.

  1. Solubility: The solubility-rating should be carried out based on the solubility of the substances in the solvents used for cleaning. The rating should be in three categories.

  1. Health Based value of API: Based on the Acceptable Daily Exposure/ Permitable Daily exposure values of the API rating should be carried out as given below.

 

 

Rating

ADE/PDE (μg/day)

1

>500

2

100 - 500

3

10 – 99

4

1 – 9

5

<1

Worst Case Rating of a Molecule (Contd.):

3. Potency of the API: The therapeutic doses are typically based on oral and/or parenteral data; the rating should be carried out as given below.

Rating

Include dose intervals (smallest therapeutic dose) ( mg )

1

>1 000

2

100 - 1 000

3

10 – 99

4

1 – 9

5

<1

The above mentioned parameters shall be multiplied with the weightage mentioned below for the calculating the total risk.

Rating

*Weightage

Rational

Solubility

3

Cleaning of a molecule depends on solubility

PDE

2

Health Based (PDE) value of the molecule is directly proportional to its adverse effects on the residue

Potency

1

Potent nature of a molecule depends on potency; Less potency more potent molecule.

Worst Case Rating of a Molecule (Contd.):

The calculation is done for better understanding:

Product Name

Parameters

Description

Rating (R)

Weightage (W)

Weighted

Risk        (R

* W)

Total score

risk

Product A (Existing)

Solubility

Very Soluble

1

3

3

12

 

PDE (μg / day)

100

2

2

4

Potency (mg)

1

5

1

5

Product B (New product)

Solubility

Practically Insoluble

3

3

9

15

 

PDE (μg / day)

100

2

2

4

Potency (mg)

100

2

1

2

Note:

  1. If the total score of the new product to be introduced is found to be greater than the existing worst case product based on risk score, then cleaning validation should be performed on one exhibit batch or 3 initial consecutive batches for commercial.
  2. If the total score of the new product to be introduced is found to be lesser than the existing worst case product based on risk score, then cleaning verification should be performed on one confirmatory batch with the existing cleaning procedure.
  3. If worst case rating of two products are same, emphasis shall be given to the product having significant color or flavor, while considering for cleaning validation.

MACO CALCULATIONS:

1. Based on Therapeutic Dose combined with a safety factor (Method-A):

Use the following equation to calculate the maximum allowable carryover.

MiniTD (A) x Mini BS (B) x RF

MACO (A-B) =   -------------------------------------------F X Maxi DD (B) Where:

MACO :  Maximum Allowable Carryover of previous product in subsequent product.

MiniTD (A) : Minimum therapeutic dose of previous product (A) manufactured (in mg)

Mini BS :  Minimum Batch Size of next product (B) (in mg )

F     : Safety Factor (1000) for OSD

Maxi DD (B): Maximum daily dose of next product (B) (in mg).

RF : Recovery Factor

MACO CALCULATIONS (Contd.):

2. Based on LD50 ( toxicology) data (Method-B): [ Toxicity based calculation shall be applied for Detergents/Cleaning Agents]

NOEL (A) x Mini BS (B)  x RF

MACO (A-B) =     ----------------------------------- or

F x Maxi DD (B)

ADI ( A) x Mini BS (B )

MACO (A-B) = --------------------------------Maxi DD (B) Where:

Acceptable Daily Intake (ADI): The ADI is the no-effect level observed, divided by the safety factor F, depending on the route of administration.

NOEL

ADI (µg/day) = ------------------------------

F

MACO : Maximum Allowable Carryover of previous product (A) in subsequent product (B).

NOEL (A) :  No observed effect level (in mg )

F      : Safety Factor (1000)

Mini BS     : Minimum Batch Size of next product (in mg)

Maxi DD (B)    : Maximum daily dose of next product (B) (in mg).

RF : Recovery Factor

MACO CALCULATIONS (Contd.):

NOEL shall be calculated as per the below formula:

NOEL=LD50 x 5. 10? 4 x n (Patient Weight in kg)

Where:

 

LD50

: Lethal dose 50 in mg/kg animal (mouse, rat.)

NOEL

: No observed effect level (in mg)

n

: Weight of average adult (50kg)

3. Based on Health Based Exposure Limits (Method-C):

It is an alternative method for establishing the limits using the PDE (Permitted Daily Exposure) values for the new drug products. The PDE is based on all the adverse effects on the patient whether pharmacological or toxicological.

PDE (A) x Mini BS (B) x RF

MACO= ---------------------------------------

Maxi DD (B)

Note: The stringent MACO value derived from the above three Methods of calculation ( i.e. Dose Based, LD50 Based and PDE based) shall be considered as acceptance criteria for Cleaning Validation , extrapolating the results upto per Swab level.

MACO CALCULATIONS (Contd.):

For example, let’s say  the following MACO ( stringent value)  value observed after calculation:

  1. Dose Based         : 2549019.0 mg
  2. LD50 Based          : 95294.0mg
  3. PDE Based            : 803634.0  mg

Now, It is evident that the stringent value obtained is basis to the LD50 based calculation , i.e. 95294.0  mg. and lets say the shared surface area of the equipment = 2430115 sq.cm

Hence, Swab limit shall be calculated as follows:

MACO (mg) x 100 x 1000  x  1

TARGET MACO (ppm)  = -------------------------------------------------------------------------------------

Shared surface area of the equipment x desorbing solvent (mL)

95294.0mg x 100 x 1000  x  1

= --------------------------------------------------

2430115  x  10

= 392.10  ppm

Now, since the calculated swab limit is more than 10 ppm, the acceptance criteria for the swab limit shall be considered as NMT10 ppm.

Sampling Procedure:

1) For Chemical Residue (swab method):

  • Swab samples shall be collected after the final cleaning of the equipment. Ensure that the equipment is visually clean before collection of samples.
  • Swab sticks shall be used for swabbing, depending on the solubility of the material as per the individual “Test Procedure” swab samples shall be collected in the relevant solvent.
  • Dip the swab in diluent in the respective test tube as identified for equipment part and squeeze it against the wall of the test tubes.
  • Swab a 100 sq.cm (10 x 10 cm) surface area of the equipment as per the following swabbing pattern in different locations as per the sampling plan.

Sampling Procedure (Contd.) :

2)  For Microbial Bioload  :

Take swab sticks in a test tube containing 10 ml of saline solution and autoclave/steam sterilizer at 121.0oC as per SOP No.GGMC259/GGMC/284

Note:

  • In case of ready to use sterile swab sticks, pre moistened the swab by dipping in sterile saline solution and squeeze excess solution by rubbing against the inner wall of the test tube and swab the area. And immediately transfer it into test tube containing sterile saline solution.
  • Collect the swab sample approximately (10 x 10 cm) on the surface of equipment / area from the places where difficult to clean, as shown in the figure below .
  • Wherever 10 x 10 cm swabbing surface is not feasible, swab the available surface area.

Sampling Procedure (Contd.) :

3)  Sampling procedure for rinse Sample :

  • For chemical residue analysis take required amount of sample solution and analyze for residue content by established/suitable method.
  • For microbial analysis, take pre sterilized sample bottles for rinse sampling.
  • Before sampling check and ensure that sample bottles have sterilization indicator status, Date of sterilization and Use before date.
  • Collect 100mL of rinse sample for the determination of Chemical residue, Clarity of Rinse Sample and pH of the rinse sample.

Formula to Calculate Rinse MACO limit:

MACO (mg) x Swabbing  Area (cm2 ) x 1000 ( conversion factor)  x RF

Swab Residue (ppm)   = Total surface Area of the Equipment in cm2 x Amount of rinsing solvent (mL)

Rinse Residue (ppm) =       MACO (mg) x Rinsing Area (cm2 ) x 1000 (Conversion factor)  x RF

Total surface Area of the Equipment in cm2 x Amount of rinsing Solvent (ml)

Consideration for Cleaning Validation:

Cleaning validation shall be conducted in case of the following , but not limited to:

  • Change in the batch size of the product.
  • Change in equipment train / Equipment surface Area.
  • New product introduction.
  • Change in process formula.
  • Decrease of Batch size of the product.

Hold Time Studies

  • Dirty/Clean hold time studies shall be performed on worst case equipment/product, based on criteria where the chances of microbial contamination are more when compared with other equipment/product using a separate protocol.
  • Equipment shall be evaluated for microbial load at different intervals before cleaning and after cleaning, after holding it for a particular period.
  • Cleaning Validation or Verification studies for campaign batches shall be conducted for the worst case product.

PRE-REQUISITES FOR CLEANING VALIDATION:

Following are the pre-requisites for conducting cleaning validation, but not limited to:

  • The equipment shall be cleaned as per the Type-C (product changeover) standard cleaning   procedure after use.
  • Cleaning validation study shall be carried out based on worst case criteria [i.e. Molecule having highest Risk Score].
  • Validated analytical methods shall be employed for cleaning validation study.
  • Personnel involved in the cleaning validation shall be trained to perform the activity i.e.

cleaning, sampling and testing.

  • Equipment surface area shall be calculated based on train of equipment shared between two products.
  • Availability of the required utilities, cleaning aids, sampling needs and qualified and trained    personal for visual inspection and sampling activities.
  • Approved protocol and validated analytical method including recovery value, swab/rinse   volumes.
  • Approved cleaning procedure for each process equipment and accessories.

 

A Typical Cleaning Validation Flow Chart:

 
   

 

 

Sampling Site Selection for a Particular Equipment:

Sampling site selection for swab sampling from a particular Equipment largely  depends upon the following:

  1. Location having the Maximum product contact surface area (For. e.g., FBE Bowl, RMG Bowl, Hoppers etc.)
  2. Location having curved surfaces , angular parts ( for e.g. Sides of Solution Preparation Vessels, Towards the Outlet of Blenders, Circular Pipes etc.
  3. Location that are difficult to clean by design complexity ( for e.g. Spiral Plates of a deduster, Feed Frame of Compression Machine, RMG Impeller and Chopper, Baffles of Blenders etc.)
  4. Locations having different MOCs other than SS ( for e.g. Gaskets)

Sampling site selection for Rinse sampling for a particular Equipment largely depends upon the following:

  1. Hard to reach location , where it is not feasible to take representative Swab samples. ( For e.g.  Large Capacity Blenders, FBE, RMGs )
  2. Closed Equipments , that cannot be dismounted to take Swab sample (for e.g. Solution Preparation Vessels,  Outlet chutes of Co-mill, Hose Pipes)
  3. Equipment’s part that contains perforations (for e.g. Screen and Meshes)

REFERENCE GUIDELINES:

  • APIC guideline [guidance on aspects of cleaning validation in active pharmaceutical ingredient plants]
  • EMEA Guideline [Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities] Ø PDA Technical Report No. 29 (Revised 2012)Points to Consider for Cleaning Validation
  • ISPE Risk based manufacture of pharmaceutical products.
  • www.Cleaningvalidation.com, for  Memos by Destin Le Blanc.

OPEN FOR DISCUSSIONS Thank You