Escolar Documentos
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Cleaning Validation
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Who Am I?
Jeff Phillips
Sr. Manager, Science and Marketing
20+ Years Pharmacology, Pharmaceutical,
Medical Device and Validation Experience
Alconox, Inc. (New York, USA)
jphillips@alconox.com
++(914)948-4040
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Chemistry of Cleaning
Chemistry of Cleaning
Chemistry of Cleaning
Chemistry of Cleaning
Detergent Selection
So for best performance (and Cleaning Method)
choose a detergent for a specific soil, substrate, or
machine/method
Environment - minimize disposal concerns, or
optimize for recycling
Safety - maximize worker safety
Economy - synergistic economical blends
Residue potential - minimum amount of synergistic
blend - least cleaner residue.
Chemistry of Cleaning
Chemistry of Cleaning
Soil Type
Natural Oils - higher alkaline cleaners
Synthetic and Petrochemical Oils - wetting,
emulsifying; typically mild alkaline
Salts, Oxides, Metals - alkaline chelating,
sequestering cleaners, best with acid cleaners
Particulates - dispersant cleaners
Protein/biofouling - protease enzyme cleaners; mild
alkaline with wetting agents
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Chemistry of Cleaning
Type Cleaner pH
Mineral acid 0-2
Mild acid
2-5.5
Typical Soils
heavy scales
salts, oxides,
metallic
Neutral
5.5-8.5 light oil and particle
Mild alkaline 8.5-11 oils, particles, films
Alkaline
11-12.5 natural oil, fat, resin
Corrosive
12.5+ heavy grease/soils
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Chemistry of Cleaning
Alkaline High pH
Generally Best cleaned by Alkaline Detergents ( in order)
Oils, fats, greases, Alcohols, Amino Acids, Some Proteins
Diols, Triols, Phosphates, Organic Acids, Acid Salts
Chemistry of Cleaning
Alkaline (High pH) cleaning mechanisms
Saponification reacting with fats, oils and esters to break
them and form water soluble salts ie. potassium hydroxide
reacts with trilauryl glycerate to form water soluble
potassium laurate and glycerine
Alkaline Hydrolysis- alkaline labile proteins are broken in to
smaller more water soluble fragments or amino acids by
alkaline attack on peptide bonds in the proteins
Alkaline Deprotonation alkaline reaction with weak acids
and alcohols to form more water soluble alkoxide salts
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Chemistry of Cleaning
Acidic Cleaning Mechanisms
Protonation acid reaction with amines, N-heterocyclics,
Pyridines, and Pyrolidines to form water soluble cationic
amine salts which are more polar molecules with greater
water solubility
Acid hydrolysis- acid reaction with starches to smaller more
water soluble monosaccharides, disaccharides and smaller
polysaccharides
Acid chelation formation of water soluble more polar
compounds with metal oxides, salts and complexes
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Chemistry of Cleaning
Residues that are both acid and alkaline labile:
proteins, polysaccharides (some cross link in alkaline)
and amine compounds
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Cleaning Validation
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Why?
Manufactured product may be harder to clean (dries, bioburden
growth)
Issues
Sometimes cleanability does NOT change with time (e.g., dry
products)
What do?
Specify a maximum hold time in cleaning
Challenge worst-case condition in validation (at least one run at
maximum)
Why?
Equipment may become re-contaminated
during storage (bioburden, dust)
Issues
If dry and sealed, should not be re-contaminated
Alternatives
Validate separately largest & smallest sizes
Validate together testing extremes
Visual examination
Key
Evaluate impact of change
May require lab work and testing to support change
Document
Computer validation
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The Tool
Calculator For Residue Acceptance Criteria
Limits For Alconox Inc. Detergents
http://www.alconox.com/calculator.html
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The Tool
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The Tool
Data needed
Detergent brand
Patient body weight
Safety Factor
Smallest next manufacturing batch
Biggest daily dose of pharmaceutical
Size of shared equipment
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The Tool
Detergent brand
Brand determines the toxicity from which a
safety based limit is determined
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The Tool
Patient Body Weight
70 kg adult
35 kg child
5 kg infant
Worst case is typically infant
Use adult or child weight if pharmaceutical is known
to only be directed at those populations
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The Tool
Safety Factor
Typically 1,000 to 10,0000
For detergents which are typically not very
hazardous, usually you use 1,000
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The Tool
Smallest next manufacturing batch
Worst case is whatever the smallest amount
that might be manufactured in the shared
equipment
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The Tool
Biggest daily dose of pharmaceutical
Use the worst case maximum daily dose.
Typically a multiple of the recommended daily
dose
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The Tool
Size of shared equipment
Measured in cm2 or L of pharmaceutical
produced
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The Tool
The calculations
Acceptable daily intake (ADI)
Safety based acceptable residue limit (ARL)
10 ppm carryover acceptable residue limit
(ARL)
Compares and selects the lower of the two
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The Tool
The calculations
ADI = LD50 mg/kg * Body Weight kg / Safety
Factor
Safety based ARL = ADI mg * smallest next
batch kg / (size of shared equipment cm2 or L
* biggest daily dose of next batch mg *
1kg/1000000 mg)
Result expressed as mg/cm2 or mg/L
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The Tool
The calculations
10 ppm carryover ARL = 10 mg residue / 1 kg
next product * (smallest next batch kg / size of
shared equipment cm2 or L)
Result expressed as mg/cm2 or mg/L
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Regulatory Support
Comprehensive cGMP compliance support
Recordkeeping documentation
Lot traceability of cleaners
Oral toxicity data
Ingredient reactivity information
Cleaner shelf-life testing
Cleaning validation support
Written cleaning procedures
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The End
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