Cleaning Validation In Pharmaceutical Industry

Cleaning validation  is a process that is gaining more & more attention day by day in the pharma industries. The reason behind its highest demand is that most of the regulatory bodies are now strict on the process of cleaning validation.
Cleaning validation is the process of validating the cleaning method or process so first have a look at what is cleaning.
 

What Is Cleaning?

The process of removing residues of previous products from any equipment used for manufacturing/packaging or area is known as cleaning. The pharmaceutical products or area can be contaminated by one of the following,

  • API Of Previous Product
  • Excipients Of Previous Product
  • Microbes
  • Airborne Particles
  • Residues Of Detergents

If all the steps and processes involved in cleaning are written and documented, it is known as cleaning method validation.

What Is Cleaning Validation?

  • Cleaning validation is a process that ensures that the method or process used for cleaning is so accurate that it removes not only residues of previous product, APIs & excipients but also removes microbes, chemicals & residues of the detergent up to defined limits.
  • Cleaning Validation is documented evidence that gives us a strong assurance that the process which we are using to clean equipment, parts, utensils or an area will produce a predetermined level of cleanliness by removing the residues of previous product, microbes and detergents.
  • The process of cleaning is documented and validated to prevent cross-contamination of manufactured products from carryover of the previous product,  microbes, chemicals or detergents.

Theme / Principle Of Cleaning Validation

The theme or basic principle of cleaning validation is as follows,

  • To give assurance that the performed cleaning activity is done in such a way that it removes all carryover or residues of previous product,  microbes or detergents or all above mentioned are removed up to the acceptance criteria.

Cleaning Validation Explanation By Simple Example

  • Cleaning validation is used to ensure that the cleaning procedure used is accurate to remove the contaminants.
  • It can easily be explained by the example of Building Construction & its inspection process to award the clearance certificate.
  • For large buildings when the construction is completed it is inspected by the inspection bodies to ensure that the contractor built it by following all the required measures and it is completely suitable to use or live in.
  • The inspectors may take some samples of concrete and marbles to ensure that the high-quality material is used during building construction.
  • On surety of all the required parameters, the building is awarded the license or certificate to use and live.
  • In the same way,any equipment in the pharmaceutical industry cleaned by the designated staff is then inspected by the inspection body to cross-check that the cleaning procedure used is adequate to fulfill the regulatory requirement.
  • The inspectors collect the samples from the surface of cleaned equipment and test it in  the Quality Control Department to ensure that the required level of cleanliness is achieved.
  • If the results of samples meet the requirements then it is said that the method used for cleaning is validated and it can be used with confidence.
 

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Importance Of Cleaning Validation

Cleaning validation importance in pharmaceutical industries can be described by some following key points,

  • Cleaning validation protocols fulfill the regulatory requirements.
  • Cleaning validation provides a high level of assurance that by using the written procedure we can achieve the same level of cleanliness all the time.
  • The cleaning validation method assures that there are no chances of cross-contamination.
  • Cleaning Validation gives surety that microbial growth is prevented.
  • With proper cleaning, equipment life is increased & downtimes are reduced.
  • Product quality is improved.

Cleaning Validation Requirements

A common question is how a cleaning validation is started? or what are the requirements for cleaning validation in pharmaceutical industries?

Following are the main requirements,

  1. Cleaning Validation Protocol
  2. Validation Team 
  3. Equipment Selection
  4. Cleaning Method 
  5. Sampling Plan
  6. Acceptance Plan

1.0 Cleaning Validation Protocol

  • For any cleaning validation process,  first of all, a protocol is prepared.
  • Cleaning validation protocol is a basic document like BMR or Batch Manufacturing Record.
  • As we know that in BMR every step is mentioned which guides us on how a batch is manufactured.
  • In the same way, the cleaning validation protocol includes all the details regarding how the cleaning validation will be performed.

Cleaning validation protocol also includes information regarding the following,

  • Cleaning Method Used
  • Amount Of water/solvent Used
  • Type Of detergent
  • Cleaning Type
  • Sampling Type
  • Sample Size
  • Analytical Method Used
  • Acceptance criteria 

2.0 Validation Team

For performing cleaning validation a team is established & the roles of each individual or department are defined.

Team Structure

The structure of the validation team may vary pharma to pharma but a basic team may consists the of following,

  • Validation Officer
  • Production Officer
  • Quality Assurance Officer
  • Quality Control Department
  • Product Development Department
  • Maintenance Department

The personnel or team involved in cleaning process validation should be trained regarding all the cleaning steps and must be aware of the cleaning protocols.

3.0 Equipment Selection

  • The equipment for which cleaning validation is to be performed is checked critically to establish how to clean.
  • The parts of equipment which are in direct contact with the product are selected for cleaning validation.
  • The parts or locations of the equipment which are difficult to clean are highlighted to ensure proper cleaning & sampling

4.0 Type Of detergent

  • The detergent used for cleaning validation should be selected carefully and those which are easily removed by rinsing are encouraged.
  • Before using any detergent its composition should be known and acceptance criteria should be given to calculate the results.

5.0 Sampling Plan

  • Sampling plays an important role during cleaning validation and the sampling plan should carefully be defined, meaning how to take samples i.e direct sampling or indirect sampling.

6.0 Acceptance Criteria

  • Before starting the cleaning validation the acceptance criteria or acceptance limit should be defined based on the product properties and size of equipment used.
  • Here swab limits and rinse samples limits are defined and our cleaning results should comply with the defined limits.

When Should Cleaning Validation be Performed?

Cleaning validation is generally performed in the following circumstances,

  • Cleaning Validation is performed first time during qualification or validation of the manufacturing process.
  • When we make any critical change in the cleaning process.
  • When there is a critical change in formulation.
  • Cleaning validation is also performed when there is a change in Equipment.
  • When there is any modification or change of cleaning agent.

FDA Guidelines For Cleaning Validation

US-FDA or U.S Food and Drug Administration describes guidelines for cleaning validation in 21 CFR section 211.67.(21 CFR cleaning validation) Section 211.67 (A) states that,

‘Equipment & utensils should be cleaned, maintained as recommended for the nature of the drug, sanitized / sterilized at suitable intervals to prevent contamination which would alter the safety, identity, strength, quality  of the drug  beyond the official or other established requirements.’

Section 211.67 (B) states that 

  • Written methods should be developed and followed for cleaning & maintenance of equipment and utensils used in manufacturing,processing,packaging and holding of drug products.

The above mentioned written procedures shall include following,

  1. Assignment of responsibility of cleaning & maintaining the equipment.
  2. Cleaning & maintenance schedule.
  3. Description of details of the method,equipment & materials used in cleaning and maintenance also include disassembling & reassembling of equipment necessary to assure proper cleaning & maintenance.
  4. Removal of previous product or batch.
  5. Protection of cleaned equipment before use.
  6. Equipment inspection for cleanliness just prior to use.

Section 211.67 (C) states that,

  • Record of cleaning & maintenance shall be maintained.

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Steps Of Cleaning Validation In Pharmaceutical Industries

For basic and easy understanding the cleaning validation after the above-mentioned requirements  is divided into the following steps

Step 1

               Cleaning

Step 2

              Sampling

Step 3 

             Testing/Analysis

Step 4

            Acceptance Criteria

Step 1

                      Cleaning

The first step in cleaning validation is the type of cleaning to be used.

  • An important point to be remembered is that Cleaning is the main activity that is to be validated in the cleaning validation process.
  • So the method used for cleaning should be acceptable and accurate.

Types Of Cleaning.

Following are main types of cleaning which are used in pharmaceutical industries for the cleaning of equipment,

  1. Manual Cleaning
  2. Cleaning In Place (CIP)
  3. Cleaning Out Of place
  4. Immersion cleaning Method
  5. Ultrasonic Cleaning

1.0 Manual Cleaning

As the name indicates it is the most traditional type of cleaning performed by hands.

It is usually the most difficult method to validate due to person to person variation.

This cleaning method consists of the following main steps,

  • Wiping with water/solvent
  • Brushing or scrubbing
  • Thorough Cleaning With Detergent
  • Rinsing with water/solvent
  • Disinfection

2.0 Cleaning In Place (CIP)

Cleaning in place is also known as CIP and it is the automated type of cleaning.

In the CIP method following are commonly used,

  • Fixed or Rotating Spray Balls
  • Washing Tank
  • Recirculating Pump
  • Detergent Tank
  • Pipings

In this type of cleaning the inputs are given and all the parameters like water quantity, water pressure, amount of detergent and drying time remain constant or fixed during all the cleaning process of a specific equipment.

3.0 Cleaning Out Of place

As the name indicates this cleaning is not done at the equipment place, here parts removed are washed and dried outside the area in a specific place using cabinets or tunnels.

4.0 Immersion Cleaning Method

In the immersion cleaning method,the equipment to be cleaned is dipped in the cleaning agent to achieve the required level of cleaning.

5.0 Ultrasonic Washing

This type of cleaning is done using ultrasonic waves to ensure proper cleaning.

Bracketing Method In Cleaning Validation

To perform Cleaning validation for all the products is not possible because it will require a lot of time and money for testing so we decide the cleaning validation for a product based on bracketing or matrix approach.

Bracketing Approach

In the bracketing approach, we select only one drug from many which are manufactured using the same equipment,procedures and may have the same class of excipients.

Worst Case Scenario In Cleaning Validation

We select the one product based on the Worst Case Scenario.Worst worst-case is also known as ‘difficult to clean’ and product for the worst case is selected on the following basis.

  • The least soluble drug product manufactured on the equipment.
  • Most toxic drug product
  • A product having a low therapeutic daily dose
  • Higher concentration of API
  • Color Product

Step 2

                    Sampling

Sampling means to take samples after cleaning of equipment which is used for manufacturing or packaging.

  • The samples are collected from the cleaned equipment and then these samples are analyzed for acceptance criteria.

Types Of Sampling Method

The sampling method used for cleaning validation in pharma may be of two types,

  • Direct Sampling Method
  • Indirect Sampling Method

Direct Sampling Method / Swab Sampling Procedure

  • In the direct sampling method, the surface Swab sampling procedure is used.
  • The swab is usually a sterile cotton bud-like structure that is physically rubbed over the hotspots or defined places of the equipment.

Swab Recovery Method

The swab recovery method is the procedure that is used to recover the residues or carryovers from the swab bud into the solvent and then it is analyzed to calculate whether it is within limits or not.

Validated Swab Recovery 

The swab recovery method used for a specific worse case drug product is validated to ensure that the residues are dissolved or recovered from the solvent or not.

During establishing a validated swab recovery method we check the following,

  • Is the solvent used, properly recover the residues or not?
  • The swabbing procedure used is accurate or not.

Procedure

  • Take swab needles or swab sticks (usually 2) according to the requirements (surface area) and dip them into a flask containing the solvent.
  • The solvent is selected according to the solubility of the worst-case drug.
  • The swab needles are pressed along the walls of the flask to remove excess solvent.
  • The swab needles are then placed in covers or vials and are closed.
  • The swab needles are then delivered to the production or packaging area where the equipment or part is to be sampled.
  • As we are validating the method, the worst-case selected drug samples are randomly applied at the surface of equipment above & below the acceptance criteria to calculate acceptance limits for swab samples.
  • The constant surface area is required for calculations so a constant area is sampled with a swab.
  • To ensure the constant area for swab the plates of SS 316L are used.
  • Usually, a 10cm×10cm plate is used so the total surface area is 100cm².
  • Place a 10cm×10cm plate on the equipment surface containing applied residues.
  • The swab stick is removed from the cover & and is rubbed inside the area of the plate from right to left or left to right.
  • Rotate the swab stick face and rub it from up to down side within the same surface area.
  • One or two swab sticks can be used depending upon the validated method
  • All the swab sticks are placed in covers & are delivered to the Validation department for testing.
  • The swabs are removed from the cover and heads or buds of the swab sticks are cut with a sterile cutter and are dipped inside the same solvent vessel which was previously used.
  • These swab bulbs or buds are stirred in the extraction solvent for some time and later are removed.
  • The solvent is then analyzed by using specified testing methods to calculate the acceptance criteria.
  • If analysis gives required results then it indicates that the method is validated and if not then the solvent used or swab procedure can be changed & again validation is done to establish a proper acceptance criteria.

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Actual Swab Sampling during Cleaning Validation / Swab Sample Collection

  • For most cases the surface of the equipment may not be smooth and it may be difficult to take swab samples in pharma from 100cm².
  •  It may be the case where surfaces are difficult to reach so here the area taken is calculated and adjustments are made for acceptance criteria according to the validated sampled area.

Cautions

  • During Swab sampling,rub swab stick only  in one direction and don’t rub the swab stick back and forth.
  • Immediately after taking swab samples, place the swab stick in the cover and close it.

Advantages Of direct Sampling

Following are some main advantages of swab or direct method of sampling,

  • Samples can easily be taken from places that are difficult to clean and are accessible.
  • If the residue is insoluble in the cleaning solvent then it can be physically removed by swab and then tested.
  • This method is also suitable for taking samples of the material which is dried out on the equipment surface.

Indirect Sampling Method / Rinse Sampling Technique

The indirect method of sampling in cleaning validation is also known as the rinse sampling technique or rinse sampling method in pharma.

In this method the equipment is rinsed with water or solvent and then this sample is tested for acceptance criteria.

During the rinse sampling technique used in pharmaceutical industries, the samples of water or solvent are taken after final cleaning and are analyzed by the method specified in the validation protocol.

In the rinse sampling technique, the amount of water used for rinsing samples and the time of rinsing is also measured.

Advantages

The advantage of this indirect method of sampling in cleaning validation is that a large surface area can be analyzed.

This method is also used for the places to take samples that are not accessible for swab samples.

Note

  • One important point to remember before sampling either by the swab or rinse method is that,first of all, organoleptic senses are used.
  • It Means visual inspection & checking the equipment  for smell or odor.
  • If the equipment is visually not cleaned or there is some type of smell or odor it means the method used for cleaning was not accurate so first ensure accurate cleaning.

Stage 3

                            Testing

For testing or  analysis, two types of methods are used,

  • Specific Method 
  • Non-Specific Method

Specific Method

For accurate testing of toxic contaminants, the specified method is used and it involves following,

  • HPLC
  • Flame Photometry
  • Titration
  • Ion Selective Electrode
  • UV spectrometry
  • Enzyme Detection

Non-Specific

It involves following,

  • pH
  • Conductivity
  • Total Organic Carbon (TOC)

Stage 4

              Acceptance Criteria

Acceptance criteria are calculations that we have done and established during method validation and then during cleaning validation, the results are compared.

Acceptance criteria can be established by following three methods,

  • Visual Inspection
  • Dose Percent
  • Parts Per Million

Visual Inspection

  • Acceptance criteria for cleaning validation by visual inspection is that there should be no visible contamination on the equipment or area.

Dose Percent

  • Not more than 0.1% of the normal therapeutic dose of one product should appear in the maximum daily dose of subsequent products.

Parts Per Million

Not more than 10 parts per million (ppm) of one product will appear or occur in another product.

Acceptance criteria should have the following properties,

  • Achievable
  • Practical
  • Verifiable
  • Scientifically Sound

Calculations Of Acceptance Criteria

Main important point to keep in mind is that acceptance criteria calculations are made before starting the cleaning validation as we discussed earlier & actual results are compared with these values.

Based On Therapeutic Daily Dose

  • This method of calculation is used when we have the value of TDD or therapeutic daily dose.
  • It is commonly used during final product changeover or cleaning.

Principle

  • The basic principle of this calculation is that the standard therapeutic daily dose of the contaminated product(next,) may be contaminated by not more than a specific proportion, usually 1/1000 of the therapeutic daily dose of the drug substance which is under investigation(previous) in cleaning validation.

MACO Method In Cleaning Validation

To establish a method for allowable carryover also known as Maximum Allowable carryover (MACO) use the following formula,

MACO =    TDD(previous) × MBS

                    SF    × TDD(next)

MACO = Maximum Allowable carryover (It is the acceptable transferred amount from the previous product)

TDD(previous) = Standard therapeutic daily dose of the investigated product in the same dosage form.

MBS = Minimum  size of Batch (Of the Next product)

TDD(next) = Standard therapeutic daily dose of the next product.

SF = Safety Factor (Usually 1000 is used)

Example

In the pharmaceutical industry,  Product A was manufactured having TDD of 15 mg with a batch size of 150 kilograms.

Cleaning was done for product B having TDD of 300 mg with a batch size of 60 kilograms.

Both are tablet products and the safety factor is 1000. 

Calculate Maximum Allowable carryover (MACO) for Product A In Product B

Use above mentioned formula as

MACO =    TDD(previous) × MBS

                    SF    × TDD(next)

Now put values according to the statement

MACO =    15(mg) × 60,000,000(mg)

                    1000   × 300 (mg)

After calculation, the answer is 3000 mg or 3 grams.

Based On Toxicological Data

During the situation where the therapeutic daily dose is not given then in those circumstances, the toxicity data are used to calculate the MACO.

This method is used for following,

  • Detergents
  • Intermediates

The calculation method used is known as NOEL

No Observable Effect Level (NOEL)

No Observable Effect Level or NOEL method is also used to calculate the MACO but first, we have to calculate the NOEL by using lethal dose as follows,

NOEL = LD⁵⁰(g/kg) 70(kG person)

                              2000

Using the NOEL value the MACO can be calculated from the following equation

MACO = NOEL × MBS

                SF × TDD(next)

MACO= This term represents Maximum Allowable Carryover.

NOEL= No Observed Effect Level

LD⁵⁰ = Lethal dose 50 g/kg

70kg = Weight Of An Average Adult

2000 = Empirical Constant

TDD(next) = Largest Normal daily dose for Next Product

MBS = Minimum  size of Batch (Of the Next product)

SF= Safety Factor

Safety factor 200 is used when API is taken Orally & it varies depending on the dosage form.

  • Safety Factor for Topical = 10-100
  • Safety Factor for Oral Products = 100-1000
  • Safety Factor for Parenterals = 1000-10,000

Limits For Swab

If we assume a homogeneous distribution then a general recommended value can be set for swabs content.

It is used for the preparation of method of analysis & limit of detection.

For whole equipment, the target value can be set using the following equation,

Target Value(ug/dm²) = MACO(ug)

                       Total Surface Area(dm²) 

Example

If MACO is 600 mg and total surface area is 1600 dm² calculate the swab value.

Solution

Put values in above 

600×1000/1600 = 375ug/dm²

Rinse Limits

The amount of residue on the equipment is assumed to be equal to the amount of residue in the rinse volume.

The rinse limit can be calculated by following

Target Value(mg/l) = MACO(mg)

                       Total Rinse Volume

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