Call Girls Coimbatore Just Call 9907093804 Top Class Call Girl Service Available
Cleaning Validation Acceptance Criteria Explained
1.
2. Cleaning Validation……………. At a glance
1Quality Assurance
üWorst Case considerations
üWorst Case considerations
ü Acceptance criteria
ü Sampling Methods
ü Analytical Methods
3. The Active Pharmaceutical Ingredient Industry involves (in general) the manufacture of Active
Pharmaceutical Ingredients by both chemical and physical means through a series of multiple
step processes. Plants or individual pieces of equipment, including ancillary equipment, may be
used in Multi-product manufacture or dedicated toindividual products.
The result of inadequate cleaning procedures is that any of a number of contaminants may be
present in the next batch manufactured on the equipment such as:
1. Precursors to the Active Pharmaceutical Ingredient.
2. By-products and/or degradation products of the Active Pharmaceutical Ingredient.
3. The previous product.
4. Solvents and other materials employed during the manufacturing process.
5. Micro-organisms, this is particularly the case where microbial growth may be sustained by theproduct.
6. Cleaning agents themselves and lubricants.
Quality Assurance
5. STAGE 4:
DEVELOP A CLEANING VALIDATION PROTOCOL FOR THE PRODUCT AND THE
EQUIPMENT BEING CLEANED
That should encompass for example:
1. Introduction
2. Scope
3. Equipment
4. Cleaning procedure
5. Sampling procedures
6. Analytical testing procedure
7. Acceptance/Cleaning limits.
8. Acceptance criteria for the validation.
STAGE 5:
GENERATE A CLEANING VALIDATION REPORT DETAILING THE ACCEPTABILITY
OF THE CLEANING PROCEDURE FOR THE EQUIPMENT AND THE PRODUCT
The report should give a full detailed background and introduction to the cleaning Validation study and
should evaluate all data generated with respect to the acceptance criteria employed for the study. The
report should also indicate the
Quality Assurance
6. 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.
2
Quality Assurance
7. Cleaning Validation…………........... Purpose
v Product integrity
Cross contamination
Microbial integrity
Product impurity
Batch integrity
v It is a regulatory requirement in Active Pharmaceutical Ingredient product
manufacture.
v Equipment reuse
v It is a customer requirement - it ensures the safety and purity of the product.
3
Quality Assurance
11. Cleaning Validation……Cleaning Parameters
q Time
q Cleaning chemistry
q Concentration
q Temperature
q Mixing / flow / turbulence
q Water quality
q Rinsing
17
Quality Assurance
12. Parameter interactions :
18
Cleaning Validation……Cleaning Parameters
Time vs Concentration :
Temp. vs Concentration :
Courtesy: Validated Cleaning Technologies for
Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
13. Parameter interactions :
19
Cleaning Validation….……Cleaning Parameters
Time vs Temperature :
Time (min)
Courtesy: Validated Cleaning Technologies for
Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
14. Cleaning Validation……Grouping Strategies
22
"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 :
ü Same manufacturing equipments being used.
ü Same cleaning SOPs being followed.
ü Similar formulations.
ü Similar risk / therapeutic group.
Equipment grouping, Cleaning method grouping, Cleaning
agent grouping, …………….., etc.
Quality Assurance
15. Cleaning Validation.……Grouping Strategies
23
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (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 E Tablet (EC) Method 4 Train A General
6 Product F Parenteral Method 2 Train C Cytotoxic
7 Product G Tablet (FC) Method 1 Train A Cytotoxic
8 Product H Tablet Method 3 Train B General
9 Product I Tablet (EC) Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
All products in a facility (hypothetical):
Quality Assurance
16. Cleaning Validation……Grouping Strategies
24
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (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 E Tablet (EC) Method 4 Train A General
6 Product F Parenteral Method 2 Train C Cytotoxic
7 Product G Tablet (FC) Method 1 Train A Cytotoxic
8 Product H Tablet Method 3 Train B General
9 Product I Tablet (EC) Method 4 Train A General
10 Product J Parenteral Method 2 Train C Cytotoxic
Before Grouping :
Quality Assurance
17. Cleaning Validation…….Grouping Strategies
25
Sr. No. Name of product Formulation
Cleaning
methods
Equipment
train
Risk / Therap.
class
1 Product A Tablet (FC) Method 1 Train A General
2 Product B Tablet Method 1 Train B General
3 Product G Tablet (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 E Tablet (EC) Method 4 Train A General
10 Product I Tablet (EC) Method 4 Train A General
After Grouping :
Quality Assurance
18. 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 / Single Therapeutic
Dosage.
Worst case eq. train : Longest train.
Worst case equipment : Larger size equipment (identical design).
Hold time studies : Longest possible duration.
Campaign Mfg. : Highest possible nos. of batches.
26
Quality Assurance
19. Three criteria :
ü It should be scientifically justifiable.
ü Pacifically achievable.
ü Methodically verifiable.
29
Possible types of limits :
v Visual
v Chemical
v Microbiological
v Endotoxin
Cleaning Validation……...Acceptance criteria
Quality Assurance
20. Visual clean criteria :
GMPs require inspection for visual cleanness before manufacture.
Key items to consider :
o Angle of view
o Distance from equipment surface
o Lighting conditions
o Viewer’s knowledge
o Surface usually must be dry
Visual aids :
Additional lighting / Magnifying glass / Mirror / Fiber-optic
scope / UV light
30
Cleaning Validation……...Acceptance criteria
Quality Assurance
21. Chemical residue limits (Therapeutically or Toxicologically
safe criteria) :
ü Therapeutic dose based criteria
Most suitable for drug product (finished product)
manufacturing facility.
ü Toxicological criteria (Where Api STD Not Available)
üMost suitable for active drug (API) manufacturing facility.
Where cleaning agents are used (other than water).
ü 10 PPM criteria
CGMP requirement widely applicable.
32
Cleaning Validation……...Acceptance criteria
Quality Assurance
22. 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 MACO (Maximum Allowable Carryover) of
Product A (Previous) to Product B (Next)
STD (A) × BS (B) × SF
MACO = (unit of mass)
LDD (B)
Where, STD = Single Therapeutic Daily Dose (Product A – ACTIVE CONTENT),
BS = batch size (Product B), SF = safety factor and LDD and LRDD = Largest Daily
Dose (Product B – DRUG PRODUCT)
33
Cleaning Validation……...Acceptance criteria
Step 1
Quality Assurance
23. Therapeutic dose based criteria :
Determination of Surface contamination (Shared Equipment)
MACO
L1 = (mass / surface area)
TSA
Where, TSA = Shared Equipment Total Surface Area (for both products)
34
Cleaning Validation……...Acceptance criteria
Step 2
Quality Assurance
24. 35
Cleaning Validation……...Acceptance criteria
Step 3
Therapeutic dose based criteria :
Determination of Sampled residue (for swab sample)
L2 = L1 × Swab Area (mass / swab)
Ø STD (Single therapeutic dose) value represents the ACTIVE drug content only.
e.g. 10 mg, the dose strength.
Ø LDD value represents the mass or volume of entire dose.
e.g. 250 mg three times a day.
Ø BS = batch size (Product B).
e.g. 150 kg.
Quality Assurance
25. Safety Factors :
36
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 products
0.0001 to 0.00001 Research, investigational products
Quality Assurance
26. 37
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 (MACO value)
Quality Assurance
29. 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 MACO
10 × BS
MACO = (unit of mass)
1000000
Where, BS = batch size (smallest available batch size)
Then use and to derive final swab residue
limit. 45
Cleaning Validation……...Acceptance criteria
Step 1
Step 3Step 2
Quality Assurance
30. 46
Cleaning Validation…………...Acceptance criteria
Step 1
10 PPM criteria (an example) :
Determination of MAC
10 × 150 kg × 1000000
MAC = = 1500 mg
1000000
The final Swab residue (L2) :
1500 mg × 25 cm2
3170 cm2
= 11.83 mg/swab
Quality Assurance
31. 47
Cleaning Validation……...Acceptance criteria
The most stringent acceptance criteria shall be chosen for
cleaning validation study (The worst case approach).
11.831932 63.00
mg / swab
In real life cases, therapeutic or 10 PPM criteria become final
acceptance criterion for cleaning validation. Quality Assurance
32. 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”
48
Cleaning Validation……...Acceptance criteria
Adminstration route TAMC Endotoxin
Oral 100 CFU/mL -
Liquid 20 CFU/mL -
Injectables 10 CFU/mL 0.25 Unit/mL
Quality Assurance
33. 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
Rinse
Easy, quick, non-intrusive, large
surface area
Limited information about
actual surface cleanliness
53
Quality Assurance
34. v Swab sampling techniques:
(⑴)One of the most widely used technique for chemical and
microbial sampling.
(⑵)Swabs are being wet with solvent aiding solubilization and
physical removal of surface residues.
(3) Results are technique dependent.
Cleaning Validation…......Sampling Methods
54
Microbial swab (sterile) Chemical swabs (Texwipe) Cotton wipes
Quality Assurance
35. v Swab sampling techniques:
(⑸)Generally 1 swab sample per location is adequate.
(⑹)Multiple swabs can be taken to improve surface recovery.
(⑺)Typical swabbed per site varies from 25 cm2 to 100 cm2. There
is no “magic” number.
(⑻)PTFE (chemically inert) templates may be used for accurate
swabbing area. e.g. (Teflon)
(⑼)“Difficult to clean” equipment surfaces
shall be identified and sampled.
(10) Representative surfaces of different
materials (MOCs) should be sampled.
Cleaning Validation……......Sampling Methods
55
10 cm
10 cm
Swab area
templates
Quality Assurance
36. v Swab sampling techniques:
(11)10 Nos. Wiping should be unidirectional at a time. Parallel
strokes should be employed to cover entire swab area.
Cleaning Validation……......Sampling Methods
56
Courtesy: Validated Cleaning Technologies for Pharmaceutical Manufacturing, D. A. LeBlanc
Quality Assurance
37. v Swab sampling techniques:
Example of “Difficult to clean” locations of an RMG:
Cleaning Validation……......Sampling Methods
57
Courtesy: Rapid mixer granulator, Kevin.
The design aspect of the equipment should be considered to
identify “difficult to clean” locations. Quality Assurance
38. v Rinse sampling techniques:
Rinse sampling involves using a liquid to cover the surfaces to be
sampled.
(⑴)One of the easy and widely used sampling method.
(⑵)Most preferable liquid for rinsing is water.
Cleaning Validation……......Sampling Methods
58Quality Assurance
39. v Specific vs non-specific methods:
(⑴)A non-specific assay may detect a variety of residues.
(⑵)A specific assay may quantify any anticipated residue.
(⑶)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
61
HPLC pH meter
Quality Assurance
40. Cleaning Validation……Analytical Methods
62
Specific Test Methods Non-Specific Test Methods
UV/Visible Spectrophotometry
Near Infrared Spectrophotometry
(NIR)
High Performance Liquid
Chromatography (HPLC)
Mid Infrared Spectrophotometry (MIR)
Atomic Absorption
Capillary Zone Electrophoresis
Enzyme Linked Immunosorbant Assay
(ELISA)
Total Organic Carbon (TOC)
pH
Titration
Conductivity
Gravimetric
Quality Assurance
41. The analytical methods used for testing cleaning samples
must be validated for [ICH Q2 (R1)]:
ü Limit of Detection (LOD)
ü Limit of Quantification (LOQ)
ü Specificity
ü Accuracy
ü Repeatability
ü Precision
ü Range
ü Linearity
ü Recovery
Cleaning Validation……Analytical Methods
63Quality Assurance
42. Recovery studies :
Procedure :
o Spike coupon with known amount
o Allow to dry
o Remove in swab or simulated rinse procedure
o For swab, desorb
o Analyze sample
o Compare to expected 100% value
This is done at surface acceptance (or below) limit.
Cleaning Validation………Analytical Methods
67
Quality Assurance
43. Minimum acceptable recovery:
v Specify in cleaning validation master plan or master protocol.
v Minimum swab recovery of 70 % - 80 %.
v Carry out recovery study for different material surfaces
(Material Of Constructions).
v Chose right wetting solvent (soluble) and absorbent swab
material to improve recovery.
Cleaning Validation………Analytical Methods
72
Quality Assurance
