cleaning validation a complete know how
DESCRIPTION
A complete illustration of Cleaning Validation is Pharmaceutical Dosage formsTRANSCRIPT
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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Quality Assurance
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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Quality Assurance
CLEANING VALIDATION…………………........... PURPOSE
Product integrity
Cross contaminationMicrobial integrityProduct impurityBatch integrity
Equipment reuse
Regulatory issues
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Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
The chemistry of contaminant removal : Solubility Wetting Emulsification Dispersion Hydrolysis Oxidation Physical removal Antimicrobial action
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Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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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Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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
Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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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Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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
Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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
Quality Assurance
CLEANING VALIDATION…………CLEANING MECHANISMS
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.
Quality Assurance
CLEANING VALIDATION……………….CLEANING AGENTS
Cleaning Agents
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Aqueous Cleaning
Organic Solvents
Water Surfactants
Chelants
Solvents (miscible)
Acids / Bases
Oxidants
Quality Assurance
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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
Quality Assurance
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
Quality Assurance
CLEANING VALIDATION…………….CLEANING METHODS
Fixed CIP :
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Quality Assurance
CLEANING VALIDATION…………….CLEANING METHODS
Portable CIP :
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Quality Assurance
CLEANING VALIDATION…………….CLEANING METHODS
Parts Washer :
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Ultrasonic Washer :
Quality Assurance
CLEANING VALIDATION…….……CLEANING PARAMETERS
Time Action Cleaning chemistry Concentration Temperature Mixing / flow /
turbulence Water quality Rinsing
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Quality Assurance
Parameter interactions :
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CLEANING VALIDATION…….……CLEANING PARAMETERS
Time vs Concentration :
Temp. vs Concentration :
Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
Parameter interactions :
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CLEANING VALIDATION…….……CLEANING PARAMETERS
Time vs Temperature :
Time (min)
Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
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
Quality Assurance
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
Quality Assurance
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.
Quality Assurance
CLEANING VALIDATION…….……GROUPING STRATEGIES
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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)
Method 4 Train A General
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)
Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
All products in a facility (hypothetical):
Quality Assurance
CLEANING VALIDATION…….……GROUPING STRATEGIES
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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)
Method 4 Train A General
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)
Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
Before Grouping :
Quality Assurance
CLEANING VALIDATION…….……GROUPING STRATEGIES
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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 GTablet (FC)
Method 1 Train A Cytotoxic
4 Product C Parenteral Method 2 Train C Cytotoxic
5 Product F Parenteral Method 2 Train C Cytotoxic
6 Product J Parenteral Method 2 Train C Cytotoxic
7 Product D Tablet Method 3 Train B General
8 Product H Tablet Method 3 Train B General
9 Product ETablet (EC)
Method 4 Train A General
10 Product ITablet (EC)
Method 4 Train A General
After Grouping :
Quality Assurance
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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Quality Assurance
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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Quality Assurance
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…………….”
Quality Assurance
Three criteria :
It should be scientifically justifiable. Pacifically achievable. Methodically verifiable.
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Possible types of limits :
Visual Chemical Microbiological Endotoxin
CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1
Quality Assurance
Therapeutic dose based criteria :
Determination of Surface contamination (Shared Equipment)
MACL1 = (mass / surface area)
SESA Where, SESA = Shared Equipment Surface Area (for both products)
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 2
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 3
Therapeutic dose based criteria :
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.
Quality Assurance
Safety Factors :
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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)
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 2
Therapeutic dose based criteria (an example) :
Determination of Surface contamination level
2000 mg
3170 cm2
= 0.63 mg / cm2 (L1 value)
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 3
Therapeutic dose based criteria (an example) :
Determination of Swab residue
0.63 mg / cm2 × 25 cm2
= 15.75 mg / swab (L2 value)
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1A
Quality Assurance
Toxicological criteria :
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1B
Consider average body weight of child where there is any pediatric dose available.
Use LD50 value of mice.
Quality Assurance
Toxicological criteria :
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1C
Step 2
Step 3
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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
Quality Assurance
10 PPM criteria :
Based on the hypothesis that 10 parts of previous product is therapeutically ineffective if presents in million parts of next product.
Determination of MAC
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1
Step 3
Step 2
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Step 1
10 PPM criteria (an example) :
Determination of MAC
10 × 150 kg × 1000000MAC = = 1500 mg
1000000
The final Swab residue (L2) :
1500 mg × 25 cm2
3170 cm2= 11.83 mg/swab
Quality Assurance
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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.
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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
Quality Assurance
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
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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
× swab area
× 25 cm2 = 3943 cfu/swab
Quality Assurance
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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CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
Quality Assurance
Determining acceptance criteria with more than one next products (The Matrix approach):
CLEANING VALIDATION…………...ACCEPTANCE CRITERIA
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
Quality Assurance
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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Quality Assurance
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.
CLEANING VALIDATION…………......SAMPLING METHODS
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Microbial swab (sterile)
Chemical swabs (Texwipe)
Cotton wipes
Quality Assurance
Swab sampling techniques:
(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.
CLEANING VALIDATION…………......SAMPLING METHODS
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5 cm
5 cm
2.5 cm
10 cm
Swab area templates
Quality Assurance
Swab sampling techniques:
(11)Wiping should be unidirectional at a time. Parallel strokes should be employed to cover entire swab area.
CLEANING VALIDATION…………......SAMPLING METHODS
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Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
Swab sampling techniques:
Example of “Difficult to clean” locations of an RMG:
CLEANING VALIDATION…………......SAMPLING METHODS
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Courtesy: Rapid mixer granulator, Kevin.
The design aspect of the equipment should be considered to identify “difficult to clean” locations.
Quality Assurance
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.
CLEANING VALIDATION…………......SAMPLING METHODS
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Quality Assurance
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.
CLEANING VALIDATION…………......SAMPLING METHODS
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Quality Assurance
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
CLEANING VALIDATION…………......SAMPLING METHODS
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Quality Assurance
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
Quality Assurance
CLEANING VALIDATION…………ANALYTICAL METHODS
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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
Quality Assurance
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
CLEANING VALIDATION…………ANALYTICAL METHODS
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Quality Assurance
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……….
CLEANING VALIDATION…………ANALYTICAL METHODS
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Quality Assurance
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
CLEANING VALIDATION…………ANALYTICAL METHODS
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Quality Assurance
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
CLEANING VALIDATION…………ANALYTICAL METHODS
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Revised swab area =
25 cm2
4.0 μg / mL
× 5.5 μg / mL
= 35 cm2 (7 cm × 5 cm)
Quality Assurance
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.
CLEANING VALIDATION…………ANALYTICAL METHODS
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Quality Assurance
Swab recovery schematic :
CLEANING VALIDATION…………ANALYTICAL METHODS
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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
Quality Assurance
Recovery calculation 1 (Spiked against Standard):
(C μg/mL) × (mL)% Recovery = × 100
(A μg/mL) × (mL)
CLEANING VALIDATION…………ANALYTICAL METHODS
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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.
Quality Assurance
Recovery calculation 2 (Spiked against Positive control) :
(C μg/mL) × (mL)% Recovery = × 100
(B μg/mL) × (mL)
CLEANING VALIDATION…………ANALYTICAL METHODS
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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.
Quality Assurance
Rinse recovery schematic :
CLEANING VALIDATION…………ANALYTICAL METHODS
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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
Quality Assurance
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.
CLEANING VALIDATION…………ANALYTICAL METHODS
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Quality Assurance
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)
Quality Assurance
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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CLEANING VALIDATION………………………HOLD TIMES
Quality Assurance
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
CLEANING VALIDATION………………………HOLD TIMES
Quality Assurance
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.
76
CLEANING VALIDATION………………………HOLD TIMES
Quality Assurance
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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.
CLEANING VALIDATION………………………HOLD TIMES
Quality Assurance
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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.
CLEANING VALIDATION………………………HOLD TIMES
Quality Assurance
CLEANING VALIDATION……………....ALL ASPECTS OF CV
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Courtesy: Biopharm international
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Cleaning Parameters
“….. cleaning of ….. has not been validated, nor is the spray temperature, volume or time defined.”
80
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
81
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
82
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
83
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
84
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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…..”
85
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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…..”
86
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Acceptance Limit
“….. acceptance criteria….shall not exceed…..μg/cm2. There is no data to justify this limit.”
87
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Sampling Locations
“Swabbing was performed on general contact areas without taking into consideration area such as edges and crevices.”
88
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Sampling Locations
“Exact / precise swab locations are not identified.”
89
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Swab Sampling
“Swab samples collected…..from different locations from each piece of equipment are combined into one sample and tested such.”
90
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
91
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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.”
92
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Dirty Equipment Hold Time
“No time frames / limitations have been established for production equipment from end of use to start cleaning.”
93
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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
CLEANING VALIDATION…………USFDA 483 CITATIONS
Recovery Studies
“Equipment cleaning validation studies for…..did not include…..present recovery studies on rinse samples.”
95
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
Recovery Studies
“…..each drug’s recovery test was performed only once, therefore there is no data to show reproducibility.”
96
Quality Assurance
CLEANING VALIDATION…………USFDA 483 CITATIONS
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
CLEANING VALIDATION…………USFDA 483 CITATIONS
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