cleaning validation a complete know how

Know – How of an Effective Cleaning Program

Sambhujyoti Das, Quality Assurance

CLEANING VALIDATION

CLEANING VALIDATION…………………... AT A GLANCE

After completing this session we’ll come to know :

Definition Purpose Cleaning mechanisms Cleaning agents Cleaning Methods Cleaning parameters Cleaning continuum Grouping strategies Worst Case considerations

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Acceptance criteria Sampling Methods Analytical Methods Hold time studies USFDA 483 Citations

CLEANING VALIDATION……………… THE DEFINITION

The process of removing contaminants from process equipment and monitoring the condition of equipment such that the equipment can be safely used for subsequent product manufacturing.

Dustin A. Leblanc.

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CLEANING VALIDATION…………………........... PURPOSE

Product integrity

Cross contaminationMicrobial integrityProduct impurityBatch integrity

Equipment reuse

Regulatory issues

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CLEANING VALIDATION…………CLEANING MECHANISMS

The chemistry of contaminant removal : Solubility Wetting Emulsification Dispersion Hydrolysis Oxidation Physical removal Antimicrobial action

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Solubility :Solubility involves the dissolution of one chemical (the contaminant) in a liquid solvent. For example, salts may be soluble in water, and certain organic actives may be soluble in acetone or methanol.

One of the primary cleaning mechanisms to be considered during design phase.

Rate of solubility, Insoluble form, Soluble – Insoluble species

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Wetting :Wetting involves the displacement of one fluid from a solid surface by another fluid. Wetting can be improved by the addition of surfactants.It improve penetration of the cleaning solution into cracks and crevices, which are usually difficult-to clean locations.

6Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc

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Emulsification :Breaking up an insoluble liquid residue into smaller droplets and then suspending those droplets throughout the water.

Emulsion = Mechanical energy + Surfactants / Polymers.

Emulsions are thermodynamically unstable (say, 5 to 10 mins.).

Redeposition of the cleaned residue back onto the equipment surfaces.

Agitation should be continued till the time to discharge the cleaning solution to the drain.

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Dispersion :Dispersion is similar to emulsification, except that it involves the wetting and deaggregation of solid particles and then the subsequent suspension of those particles in water.More important in dry product manufacturing.

Hydrolysis :This involves the cleavage of certain bonds in an organic molecule.

The resultant hydrolyzed residues must either be water soluble or solubilized at the pH of the cleaning solution. 8

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Oxidation :This involves the cleavage of various organic bonds, such as carbon-carbon bonds, by the action of a strong oxidizing agent.Large Non-polar Mol. Smaller more polar Mol.

Antimicrobial Action :Mechanisms that may kill organisms but leave behind nonviable microbial residues.Special type of mechanism, sterilization, disinfection. 9

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Physical Removal:Cleaning by some mechanical force. the objective is to physically displace the residue.Pressurized water + Scrubbing

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In real life situation, more than one cleaning mechanisms are being used.

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CLEANING VALIDATION……………….CLEANING AGENTS

Cleaning Agents

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Aqueous Cleaning

Organic Solvents

Water Surfactants

Chelants

Solvents (miscible)

Acids / Bases

Oxidants

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CLEANING VALIDATION……………….CLEANING AGENTS

Organic Solvents

• Acetone• Methan

ol• Ethyl

Acetate

Surfactants

• SLS• SDS• Fatty

acid salts

Chelants

• EDTA• NTA• SHMP

Solvents (miscibl

e)• Glycol

Ethers

Bases

• NaOH• KOH

Acids

• Glycolic Acid

• H3PO4

• Citric Acid

Oxidants

• NaOCl• Peraceti

c Acid• H2O2

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CLEANING VALIDATION…………….CLEANING METHODS

Automated Cleaning:

o Fixed CIPo Portable CIPo Parts Washero Ultrasonic

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Manual Cleaning: Soak Brush Wipe Spray

Extent of automation……………..Extent of disassembly

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Fixed CIP :

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Portable CIP :

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Parts Washer :

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Ultrasonic Washer :

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CLEANING VALIDATION…….……CLEANING PARAMETERS

Time Action Cleaning chemistry Concentration Temperature Mixing / flow /

turbulence Water quality Rinsing

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Parameter interactions :

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Time vs Concentration :

Temp. vs Concentration :

Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc

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Parameter interactions :

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Time vs Temperature :

Time (min)


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CLEANING VALIDATION…….……CLEANING CONTINUUM

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Continuum represent the extremes in the range of operating differences found within the industry. The continuum should be used during the initial phases of defining a cleaning validation program or during new product development.Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Automated CleaningCOP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..CIPDedicated Equipment . . . . . . . . . . . . . Non-Dedicated EquipmentProduct Contact Surfaces . . . . . . . Non-Product Contact SurfacesNon-Critical Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Critical SiteMinor Equipment . . . . . . . . . . . . . . . . . . . . . . . . Major Equipment

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CLEANING VALIDATION…….……CLEANING CONTINUUM

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Low Risk Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . High Risk DrugsHighly Characterized . . . . . . . . . . . . . . . . . . . Poorly CharacterizedSterile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-SterileSolid Formulations . . . . . . . . . . . . . . . . . . . . . Liquid FormulationsSoluble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . InsolubleSingle Product Facility . . . . . . . . . . . . . . . Multiple Product FacilityCampaigned Production . . . . . . . . . Non-Campaigned ProductionSimple Equipment Train . . . . . . . . . . . Complex Equipment Train

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CLEANING VALIDATION…….……GROUPING STRATEGIES

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"Grouping" is the concept of demonstrating that certain elements of cleaning are of a similar type, and selecting one (or more) representative object(s) on which to conduct the Cleaning Validation (Cleaning Process Qualification).

Product grouping :

Same manufacturing equipments being used. Same cleaning SOPs being followed. Similar formulations. Similar risk / therapeutic group.

Equipment grouping, Cleaning method grouping, Cleaning agent grouping, …………….., etc.

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Sr. No.

Name of productFormulat

ionCleaning methods

Equipment train

Risk / Therap.

class

1 Product ATablet (FC)

Method 1 Train A General

2 Product B Tablet Method 1 Train B General

3 Product C Parenteral Method 2 Train C Cytotoxic

4 Product D Tablet Method 3 Train B General

5 Product ETablet (EC)


6 Product F Parenteral Method 2 Train C Cytotoxic

7 Product GTablet (FC)

Method 1 Train A Cytotoxic

8 Product H Tablet Method 3 Train B General

9 Product ITablet (EC)


10 Product J Parenteral Method 2 Train C Cytotoxic

All products in a facility (hypothetical):

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Sr. No.


ionCleaning methods

Equipment train

Risk / Therap.

class















Before Grouping :

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Sr. No.


ionCleaning methods

Equipment train

Risk / Therap.

class















After Grouping :

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CLEANING VALIDATION…..WORST CASE CONSIDERATIONS

Once the product groups have been established, the next step is to determine the so-called “worst case” representative of each group.

It is that member(s) who shows the highest challenge on cleaning program.

Worst case product : Toxicity / solubility / highly characterized / difficult to clean ingredients.

Worst case eq. train : Longest train.Worst case equipment : Larger size equipment

(identical design).Worst case acc. criteria: Stringent acceptance

criteria.Hold time studies : Longest possible

duration.Campaign Mfg. : Highest possible nos. of

batches.

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CLEANING VALIDATION…..WORST CASE CONSIDERATIONS

There is no ‘hard & fast’ rule on worst case selection.

A good logic and science should always be used.

Grouping and worst case selection help to demonstrate cleaning method robustness.

It smartly reduces the load from cleaning validation program.

These philosophies should always be verified against the actual capability of cleaning program.

The ultimate ‘cost – benefit’ ratio should be evaluated.

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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA

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How clean is clean ?What are the bases of defining

limits ?What are the impacts of after

cleaned residue ?Human Drug CGMP Notes, 9:2, 2Q 2001 :“Should equipment be as clean as the best possible method of residue detection or quantification?”

Answer: “No,……absolute cleanliness is neither valuable nor feasible…. It should be as clean as can be reasonably be achieved, to a residue limit that is medically safe and that causes no product quality concerns…………….”

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Three criteria :

It should be scientifically justifiable. Pacifically achievable. Methodically verifiable.

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Possible types of limits :

Visual Chemical Microbiological Endotoxin


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Visual clean criteria :

GMPs require inspection for visual cleanness before manufacture.

Key items to consider :o Angle of viewo Distance from equipment surfaceo Lighting conditionso Viewer’s knowledgeo Surface usually must be dry

Visual aids :Additional lighting / Magnifying glass / Mirror / Fiber-optic scope / UV light 3

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Application for visual limits :

A typical visual limit is NLT 4 μg / cm2.

“Visually clean” may not be enough by itself Potent drugs Microbial contamination Endotoxin

More suitable method for non-potent drug products and APIs.

PIC/S advocates spiked coupon study for determination of visual inspection limits (and for training of inspectors). 3

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Chemical residue limits (Therapeutically or Toxicologically safe criteria) :

Therapeutic dose based criteriaMost suitable for drug product (finished product) manufacturing facility.

Toxicological criteriaMost suitable for active drug (API) manufacturing facility.Where cleaning agents are used (other than water).

10 PPM criteriaCGMP requirement widely applicable. 3

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Therapeutic dose based criteria :

Based on the assumption that 1/1000 part of therapeutic dose does not have any clinical impact on human (animal) body.

Determination of MAC (Maximum Allowable Carryover) of Product A (Previous) to Product B (Next)

SRDD (A) × BS (B) × SFMAC =

(unit of mass) LRDD (B)

Where, SRDD = Smallest Recommended Daily Dose (Product A – ACTIVE CONTENT), BS = batch size (Product B), SF = safety factor and LDD and

LRDD = Largest Recommended Daily Dose (Product B – DRUG PRODUCT)

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Step 1

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Determination of Surface contamination (Shared Equipment)

MACL1 = (mass / surface area)

SESA Where, SESA = Shared Equipment Surface Area (for both products)

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Step 2

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Step 3


Determination of Sampled residue (for swab sample)

L2 = L1 × Swab Area (mass / swab)

SRDD value represents the ACTIVE drug content only.

e.g. 5 mg or 10 mg, the dose strength.

LRDD value represents the mass or volume of entire dose.

e.g. 250 mg or 20 mL (drug + excipients).

Convert similar items into similar convenient unit of measure.

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Safety Factors :

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Approach Approach Typically Applicable To

0.1 to 0.01 Topical products

0.01 to 0.001 Oral products

0.001 to 0.0001 Parenterals, opthalmic products

0.0001 to 0.00001

Research, investigational products

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Step 1

Therapeutic dose based criteria (an example) :

Determination of Maximum Allowable Carryover

10 mg × 150 kg × 0.001 × 1000000

(250 mg × 3)

= 2000 mg (MAC value)

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Step 2


Determination of Surface contamination level

2000 mg

3170 cm2

= 0.63 mg / cm2 (L1 value)

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Step 3


Determination of Swab residue

0.63 mg / cm2 × 25 cm2

= 15.75 mg / swab (L2 value)

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Toxicological criteria :

Based on the toxicological information available in Material Safety Data Sheets.

Determination of NOEL (No Observed Effect Level)

NOEL = LD50 × Emperical Factor

(unit of mass/kg of body weight)

Where, LD50 = lethal dose for 50% of animal population in study (mg/kg/day), Emperical Factor = derived from animal model developed by

Layton, et.al : 0.001*

* Used by expert panel of WHO (10-3).

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Step 1A

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Determination of ADI (Acceptable Daily Intake)

ADI = NOEL × AAW × SF

(unit of mass)Where, AAW = average adult weight : 70 kg,

SF = safety factor (0.01)

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Step 1B

Consider average body weight of child where there is any pediatric dose available.

Use LD50 value of mice.

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Determination of MAC (Maximum Allowable Carryover)

ADI × BSMAC =

LRDD (any next product)(unit of mass)

Then use and to derive final swab residue limit.

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Step 1C

Step 2

Step 3

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Step 1A

Toxicological criteria (an example) :

Determination of NOEL

(1750 mg /kg/day) × 0.001 = 1.75 mg/kg (NOEL

value)

Determination of ADI

(1.75 mg/kg) × 70 kg × 0.01 = 1.225 mg

(ADI value)

Step 1B

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Step 1C

Toxicological criteria (an example) :

Determination of MAC

1.225 mg × 150 kg × 1000000

(250 mg × 3)

= 245000 mg

The final Swab residue (L2) :

245000 mg × 25 cm2

3170 cm2= 1932 mg/swab

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10 PPM criteria :

Based on the hypothesis that 10 parts of previous product is therapeutically ineffective if presents in million parts of next product.


10 × BSMAC =

(unit of mass) 1000000

Where, BS = batch size (smallest available batch size)

Then use and to derive final swab residue limit.

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Step 1

Step 3

Step 2

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Step 1

10 PPM criteria (an example) :


10 × 150 kg × 1000000MAC = = 1500 mg

1000000

The final Swab residue (L2) :

1500 mg × 25 cm2

3170 cm2= 11.83 mg/swab

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The most stringent acceptance criteria shall be chosen for cleaning validation study (The worst case approach).

11.83

15.75

1932

mg / swab

In real life cases, therapeutic or 10 PPM criteria become final acceptance criterion for cleaning validation.

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Microbiological criteria : Internal specifications Official specifications: e.g. USP <1111>, “Microbial Examination of nonsterile Products: Acceptance criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use”

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Adminstration route

Total aerobic count (cfu/g or

cfu/mL)

Total combined

yeasts/molds count (cfu/g or

cfu/mL)

Nonaqueous oral 103 102

Aqueous oral 102 10

Most topicals 102 10Quality Assurance

Microbiological criteria : Environmental specifications: EU GMP, Annex – 1, “Recommended limits for microbiological monitoring of clean areas during operation”

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GradeContact plates (diam. 55 mm),

cfu/plate

A < 1

B 5

C 25

D 50

i.e. recommended limit for microbial contamination in grade D area is : 50/{π × (5.5/2)2}= 2.10 cfu/cm2

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Microbiological criteria from internal specifications: Driven by SOP. Must be backed up by justifiable scientific rationale.

Microbiological criteria from official specifications:

Spec. limit × factor × Wt. product

SESA

An example:

1000 cfu/g × 0.1 × 5 kg × 103

3170 cm2

50


× swab area

× 25 cm2 = 3943 cfu/swab

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Microbiological criteria from environmental specifications:

50/{π × (5.5/2)2} × swab area

An example:

2.10 cfu/cm2 × 25 cm2 = 52 cfu/swab

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Determining acceptance criteria with more than one next products (The Matrix approach):


NEXT PRODUCT Prod. A

Prod. B

Prod. C

Prod. D

Prod. E

(kg) B. Size 200.0 75.0 100.0 150.0 355.5

(cm2) S. Area 4525 3960 4015 3770 4008

(mg) SRDD LRDD GENERAL SOLID FACILITY

Product A 10.0 450.0 10.5 13.8 22.1 49.3

Product B 1.0 320.0 3.4 1.9 3.1 6.9

Product C 25.0 600.0 46.0 19.7 41.4 92.4

Product D 5.0 300.0 18.4 7.9 10.4 36.9

Product E 125.0 800.0 172.6 74.0 97.3 155.4

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PREVIOUS

PRODUCT

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The sampling procedure refers to the method of collecting the residues from the surface so that they can be measured.

CLEANING VALIDATION…………......SAMPLING METHODS

Types Advantages Limitations

Swabs & Wipes

Dissolves & physically removes sample, adaptable to wide variety of area

May introduce fibers, technique dependent, hard-to-reach areas

RinseEasy, quick, non-intrusive, large surface area

Limited information about actual surface cleanliness

CouponNon-technique dependent, reduces variability in recovery

Invasive, might interfere with cleaning process

PlaceboPlacebo contacts the same surfaces as the product

Difficult to determine recovery

Direct Surface

Rapid, non-invasive, economical

Some techniques not widely developed

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Swab sampling techniques:

(1)One of the most widely used technique for chemical and microbial sampling.

(2)Swabs are being wet with solvent aiding solubilization and physical removal of surface residues.

(3)Results are technique dependent.


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Microbial swab (sterile)

Chemical swabs (Texwipe)

Cotton wipes

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(5)Generally 1 swab sample per location is adequate.

(6)Multiple swabs can be taken to improve surface recovery.

(7)Typical swabbed per site varies from 25 cm2 to 100 cm2. There is no “magic” number.

(8)PTFE (chemically inert) templates may be used for accurate swabbing area.

(9)“Difficult to clean” equipment surfaces shall be identified and sampled.(10) Representative surfaces of different materials (MOCs) should be sampled.


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5 cm

5 cm

2.5 cm

10 cm

Swab area templates

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(11)Wiping should be unidirectional at a time. Parallel strokes should be employed to cover entire swab area.


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Example of “Difficult to clean” locations of an RMG:


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Courtesy: Rapid mixer granulator, Kevin.

The design aspect of the equipment should be considered to identify “difficult to clean” locations.

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Rinse sampling techniques:

Rinse sampling involves using a liquid to cover the surfaces to be sampled.(1)One of the easy and widely used sampling

method.(2)Most preferable liquid for rinsing is water.(3)The rinse volume is an important factor that

has to be determined.

Rinse volume α (1/Residue conc. in rinse sample)

(4) Forced rinsing is advisable for collection of less soluble residues.


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Determination rinse volume:

(1)Variability in magnitudes of surface areas gives rise of variable residue concentrations in rinse samples (fixed rinse volume).

(2)Variable acceptance criteria for a single product creates confusion.

(3)It is a good idea to chose variable rinse volumes to keep constant residue concentration in rinse samples (fixed acceptance criteria).

Formula : L1 × ESA

Rinse vol. for Equipment A = Anticipated rinse

conc.


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Determination rinse volume:

Example : 0.63 mg / cm2 ×

1760 cm2

Rinse vol. for Equipment A = 10 μg / mL

= 110.9 L (considering mg/L = PPM)

0.63 mg / cm2 × 810 cm2

Rinse vol. for Equipment B = 10 μg / mL

= 51.0 L


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Specific vs non-specific methods:

(1)A non-specific assay may detect a variety of residues.

(2)A specific assay may quantify any anticipated residue.

(3)It is essential to correlate the results from a specific method to the results from other non-specific methods that might be used for routine monitoring of cleaning effectiveness.

CLEANING VALIDATION…………ANALYTICAL METHODS

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HPLC

pH meter

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Specific Test Methods Non-Specific Test Methods

UV/Visible SpectrophotometryNear Infrared Spectrophotometry (NIR)High Performance Liquid Chromatography (HPLC)Mid Infrared Spectrophotometry (MIR)Atomic AbsorptionCapillary Zone ElectrophoresisEnzyme Linked Immunosorbant Assay (ELISA)

Total Organic Carbon (TOC)

pHTitration

ConductivityGravimetric

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The analytical methods used for testing cleaning samples must be validated for [ICH Q2 (R1)]:

Limit of Detection (LOD) Limit of Quantification (LOQ) Specificity Accuracy Repeatability Precision Range Linearity Recovery


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The analytical method used for evaluation of cleaning sample is different that used for product assay.

If the target limit in the analytical sample were 5.2 μg / mL, and a method was only able to detect down to 7.0 μg / mL, that method would not be useful for cleaning validation purposes.

The target value should be within the linearity range of the specific method.

What if the calculated acceptance value is less than the detectable level of an analytical method?There may be two options available……….


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Choose more efficient analytical method !

Example: Derived acceptance limit = NMT 4.0 μg / mLAnalytical LOQ = 5.5 μg / mLAnalytical Method = UV/Visible Spectrophotometry

New method adopted = Ion mobility spectrometry

New LOQ = 2.0 μg / mL


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Increase the sampling area to achieve at least LOQ value!

Example: Derived acceptance limit = NMT 4.0 μg / mLAnalytical LOQ = 5.5 μg / mLSwab area = 25 cm2


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Revised swab area =

25 cm2

4.0 μg / mL

× 5.5 μg / mL

= 35 cm2 (7 cm × 5 cm)

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Recovery studies :Procedure :o Spike coupon with known amounto Allow to dryo Remove in swab or simulated rinse procedureo For swab, desorbo Analyze sampleo Compare to expected 100% value

This is done at surface acceptance (or below) limit.


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Swab recovery schematic :


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1. Spike control diluent directly

ControlB

μg/mL

ControlC

μg/mL

Standard

solutionA

μg/mL

2a. Spike

coupon

2b. Swab

coupon

2c. Extract swab

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Recovery calculation 1 (Spiked against Standard):

(C μg/mL) × (mL)% Recovery = × 100

(A μg/mL) × (mL)


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Recovery depends on spiked standard of known concentration. Disorbing solvent may be of any volume (mL). Recovery depends on material surface,

sampling method and some what on analytical method.

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Recovery calculation 2 (Spiked against Positive control) :

(C μg/mL) × (mL)% Recovery = × 100

(B μg/mL) × (mL)


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More useful if defined standard is not readily available.

Swab recover study with multiple analysts : Usually 3 replicates by one sampler. Use lowest value of any one run.

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Rinse recovery schematic :


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Pipette with rinse

solution (known volume)

Spiked coupon

Collection beaker

Spike bottom of SS beaker

Lab sheker

Case 1 Case 2

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Minimum acceptable recovery:

Specify in cleaning validation master plan or master protocol.

Minimum swab recovery of 70 % - 80 %. Minimum rinse recovery of 50 %. Carry out recovery study for different material

surfaces (Material Of Constructions). Chose right wetting solvent (soluble) and

absorbent swab material to improve recovery. May allow <50 % recovery with written

justification.


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o DEHT = Max. allowed time, between end of usage and employing cleaning

o CEHT = Max. allowed time, between end of cleaning and further usage

CLEANING VALIDATION………………………HOLD TIMES

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Cleaning Hold Time studies

Cleaned Equipment Hold Time

(CEHT)

Dirty Equipment Hold Time

(DEHT)

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Dirty equipment hold time study (DEHT) :

Soils may become more difficult to clean over time.

Maximum DEHT should be in SOPs. Maximum time shall be set in conjunction with

production. Representative / worst case product can be

selected for study. Equipments support wet processing can be

selected. If extra cleaning is desirable, then it should be

in SOP. May be expressed in days but preferably by

hours. Three runs at maximum time……..safe harbor.

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Dirty equipment hold time study (DEHT) :

Method

Carry out microbiological sampling at 24 hr., 48 hr., 36 hr., …... from the dirty equipments.

Clean the equipments as per SOPs. Carry out chemical sampling after cleaning. Compile all results (chemical and microbial). Successful results shall standardize the

maximum DEHT. Failure of any results shall reduce the max.

DEHT followed by another 3 verification runs. 75


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Cleaned equipment hold time study (CEHT) :

Microbiological evaluation is the key focus area. Maximum CEHT should be in SOPs. Representative / worst case product can be

selected for study. Vitamins, nutritional supplements, product

containing Starch or Gelatin may represent worst cases.

Avoid conducting study on antibiotic or antimicrobial products.

Three runs at maximum time……..safe harbor. Protection during storage of cleaned

equipments should be as per SOPs.

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Cleaned equipment hold time study (CEHT) :

Method

Clean the equipments as per SOPs. Store under protection (as per routine

procedure). Carry out microbiological sampling at 24 hr., 48

hr., 36 hr., …... Verify the results against limit (less than

validation limit). Successful results shall standardize the

maximum CEHT. Failure of any results shall reduce the max.

CEHT followed by another 3 verification runs. Do not set max. CEHT on “until failure” basis.


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Campaign hold study (CHS) :

Cleaning after production of definite number consecutive batches.

Negotiate with production related to number of batches.

Simulate max. anticipated hours of campaign production.

Cumulative deposition of residues may accelerate product degredation.

Perform cleaning and sampling at the end of campaign.

Max. CHS (no. of batches + time) should be in SOPs.

Batch to batch or lot to lot cleaning is advisable. More suitable for dedicated product

equipments.


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CLEANING VALIDATION……………....ALL ASPECTS OF CV

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Courtesy: Biopharm international

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CLEANING VALIDATION…………USFDA 483 CITATIONS

Cleaning Parameters

“….. cleaning of ….. has not been validated, nor is the spray temperature, volume or time defined.”

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Time of Cleaning

“Equipment cleaning is performed on a “clean until clean” basis. There has been no determination of the number of cleanings required to ensure the cleanliness of the equipment.”

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Manual Cleaning

“Hands on training for equipment cleaning operations is not provided and there is no program in place to assure cleaning consistency between operators.”

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Cleaning Log

“There is no assurance that cleaning is conducted as stated in their SOPs…… There are no cleaning logs to indicate that this has been done.”

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Poor Cleaning

“….. we observed foreign material on the filter grates….. Daily cleaning as per SOP…..failed to remove the material. End of process cleaning as per SOP…..failed to remove the material. Weekly cleaning as per SOP……failed to remove the material.”

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Detergent Concentration

“Detergent is dispensed into the ……Stopper Washer reservoir every third cycle. No data has been collected to determine the detergent concentration each cycle…..”

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Cleaning Agent Labeling

“The firm’s control over IPA 100% used to clean equipment in production is inadequate. …..bottles are not labeled…..with date, expiration or who dispensed, ….no scientific information….which would establish an expiration date…..”

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Acceptance Limit

“….. acceptance criteria….shall not exceed…..μg/cm2. There is no data to justify this limit.”

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Sampling Locations

“Swabbing was performed on general contact areas without taking into consideration area such as edges and crevices.”

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Sampling Locations

“Exact / precise swab locations are not identified.”

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Swab Sampling

“Swab samples collected…..from different locations from each piece of equipment are combined into one sample and tested such.”

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Rinse Sampling

“….firm’s validation…..is inadequate in that the rinse solutions were not analyzed for the presence of the active ingredient residues that might be present.”

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Rinse Sampling

“There is not an exact sampling procedure for the collection of rinse water samples which takes into account the surface area involved, time of contact….., volume of rinse, and temperature of rinse, along with a formula to calculate the amount of possible contamination based on analysis.”

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Dirty Equipment Hold Time

“No time frames / limitations have been established for production equipment from end of use to start cleaning.”

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Quality Assurance


Cleaned Equipment Hold Time

“A time limit for the length of time allowed between cleaning and the use of the manufacturing equipment…..has not been established.”

94

Quality Assurance


Recovery Studies

“Equipment cleaning validation studies for…..did not include…..present recovery studies on rinse samples.”

95

Quality Assurance


Recovery Studies

“…..each drug’s recovery test was performed only once, therefore there is no data to show reproducibility.”

96

Quality Assurance


Recovery Studies

“Your firm is using the average of recovery results (from different amounts of spiked solution) instead of the worst case result. Using a value that represents the average does not ensure that contamination is not higher than calculated.”

97

Quality Assurance


Change Control

“The SOP has been revised twice. No review was performed to determine if a re-validation was necessary for the changes……”

98

Quality Assurance

CLEANING VALIDATION……………................................???

Are we missing anything

Quality Assurance

CLEANING VALIDATION……...SOURCES OF INFORMATION

“Guide to Inspections Validation of Cleaning Processes”, Inspection note by FDA (US).

“Recommendation on VMP, IQ and OQ, non-sterile process validation and cleaning validation”, (PIC/S).

“GMP guide for API”, (ICH, Q7). “Guidance on Cleaning Validation”, Health

Canada.

Technical sources : Points to Consider for Cleaning Validation, PDA

29. Points to Consider for Biotechnology Cleaning

Validation, PDA 49 Sambhujyoti Das, Quality Assurance

100

CLEANING VALIDATION

cleaning validation a complete know how

Healthcare