2546

(Guide to Cleaning Validation)

1 .. 2546

 1,000

ISBN 974-294-552-7

1. .
2. .
3.
4. .
5.
6.
7. .
8. .

4

1. (Product Development Recommendation for
Semisolid Dosage Forms)
2. (Guide to
Pharmaceutical Process Validation of Solid Dosage Forms)
3. (Guide to Cleaning Validation)
4. (Guide
to Validation of Heat Sterilization Process)

4
4

2546

1. (INTRODUCTION) ................................................................................................................... 1
2. (CONTAMINATION)..................................................................................................... 1
2.1.
(Types of Contamination) ................................................................ 1
2.2.
(Control of Contamination).......................................................... 2
3. (CLEANING)........................................................................................................ 3
3.1.
(Cleaning Objective)................................................. 3
3.2.
(Cleaning Mechanism)................................................................ 4
3.3
(Cleaning Agents) .................................................................. 4
3.4.
(Level of Cleaning) ............................................................ 6
3.4.
(Cleaning Procedure) ...................................................................... 6
4. (CLEANING VALIDATION) ............................ 8
4.1.
(Cleaning Validation Objective) ......................... 9
4.2.
(Cleaning Validation Protocol)... 9
4.3.
(Worst Case) ................... 10
4.4.
(Sampling).............................................................................. 14
4.5.
(Analytical Method).......................................................... 16
4.6.
(Revalidation) .................................................................... 21
4.7.
(Result and Report).................................................................................... 21
4.8.
(Acceptance Criteria) ............................................................................ 21
5. (GLOSSARY) ................................................................................................................... 23
6. (BIBLIOGRAPHY)...................................................................................................... 25

Cleaning Validation

1. (INTRODUCTION)
(Cleaning)

(Good Manufacturing
Practices, GMP)

(safety)



(Cleaning Validation)


( AZT .. 2537) .. 2543
Cleaning validation

2. (CONTAMINATION)
2.1. (Types of Contamination)
3
2.1.1. (Chemical Contamination Cross Contamination)




2.1.2. (Physical Contamination)
fiber

2.1.3. (Microbiological Contamination Bioburden

Biocontamination)
1

Cleaning Validation

2.2. (Control of Contamination)

(Facilities) (Equipment) (Personnel) (Material)
(Waste)
2.2.1. GMP


2.2.2. GMP



GMP

(Drainable)

Cleaning Validation

2.2.3.
GMP


2.2.4.

3. (CLEANING)
(Cleaning)

3.1. (Cleaning Objective)

3.1.1.
(residue) (contaminants)
, , ,

3.1.2.

3.1.3. (GMP)
3.1.4. ,
,

Cleaning Validation

3.2. (Cleaning Mechanism)

(Cleaning Mechanisms) 5
3.2.1. (Mechanical Action)

3.2.2. (Dissolution)

(Organic solvent)
2
3.2.3. (Detergency) (Surfactant)
(Detergent) 4 (Wetting agent)
(Solubilizers) (Emulsifier)
(dispersants)
3.2.4. (Chemical reaction) oxidation , hydrolysis

sodium hypochorite oxidation

3.2.5. (Antimicrobial Action)

3.3 (Cleaning Agents)

o
o
o

o
o (Rinse)
o

4

Cleaning Validation

o
(Cleaning Solution) 2
3.2.6. (Organic Solvent Cleaners)

3.2.7. (Aqueous Based Cleaners)

- 95 % (Cleaning Solution)
-
oxidation hydrolysis

! pH 6 9

! stainless steel pH

!


sodium hydroxide

3.4. (Level of Cleaning)

2

Cleaning Validation

3.4.1 (Major Cleaning)

(Cleaning Validation)


3.4.2 (Minor Cleaning)

batch (strength)


(
)



(Dedicated or Unshared Equipment)

(Non dedicated or Shared Equipment)

3.5. (Cleaning Procedure)

3.5.1. (Manual)

(Hand Tool)

Cleaning Validation

I. (Disassembly)
II. (Pre-wash)
III. (Wash)
IV. (Rinse)
V. (Final Rinse)
VI. (Drying)
VII. (Visual Inspection)
VIII. (Reassembly)
3.5.2. (Semi Automated Cleaning)

3.5.3. (Automated Cleaning)

3.5.4. (Porous Equipment)


(sampling)

3.5.5. (Placebo) (placebo)

placebo

Cleaning Validation

Cleaning in Place (CIP)

(Automated
Cleaning)

CIP CIP

pH
CIP
IX. (Pre-wash)
X. (Wash)
XI. (Blow out)
XII. (Rinse)
XIII. (Final Rinse)
XIV. (Blow out)
XV. (Drying)
Cleaning out of Place (COP)


(Manual)

4. (CLEANING VALIDATION)

Cleaning Validation

(High Sensitivity)



(Acceptance Criteria)

Cleaning validation

3.4. (Cleaning Validation Objective)

3.5. (Cleaning Validation
Protocol)
Cleaning validation protocol

Standard Operating
Procedure (SOP) , Guideline Master Plan
protocol :
-
- (Validation Policy)
-
-
-
9

Cleaning Validation

- (Validation Plan)

(Schedule)
-
- (Sampling)
- (Analytical Method)
- Cleaning agent detergents solvents
-

- (Acceptance Criteria)
- (Revalidation)

3.6. (Worst Case)

Worst case
Bracketing

4.6.1. Worst case


(solubility)

(strength)
10

Cleaning Validation

Worst case
4.6.2. Worst case

Worst case

11

Cleaning Validation

High Shear Mixer

Diosna

Dry Granulator

Compactor

Inner side of lid

Lid gasket
Inner side of discharge value
Bottom of blades
Impeller blades
Chopper blades
Vent filter
Feed hopper
Dosing spiral
Rollers
Oscillating blades
Screen

Drying

Fluid Bed Dryers

Glatt

Tray Ovens

All

Trolley window
Upper cylinder wall
Trolley gasket
Filter bags
Tray Corners
Exhaust air duct or grill

Particle size reduction

Cutting Mills

Fitzpatrick

Cutting blades
Screen

Screening Mills

Oscillating (Frewitt)

Oscillating blades
Screen
Rotor blades
Screen

Rotating

12

Cleaning Validation

Blenders

Diffusion Mixers

V-blender

Bins

All

Inner side of lid

Lid gasket
Inner side of discharge value
Intensification bar
Inner side of Lid
Inner side of discharge value

Unit dosing
Tablet Press

All

Capsule Filling Machine

Powder Filler

All
Volume fill
Auger fill
Auger fill

Coating

Pan

All

Fluidized Bed

Glatt

Pan
Exhaust air duct
Dosing pump
Baffles
Trolley window
Upper cylinder wall
Trolley gasket
Filter bags
Dosing pump

Feed hopper
Force feeder
Punch and die
Feed hopper
Piston
Plate filler
Feed hopper
Dosing spiral
Dosing funnel

13

Cleaning Validation

3.7. (Sampling)
Cleaning Validation
(Cross Contamination)
(Sampling)

(Sampling Diagram)
Check List

(Worst Case)
(Sampling Technique)
Recovery Recovery
Recovery


4.7.1. Swabs and Wipes
Swab
Ethyl Alcohol
Sampling Diagram Check List

-
-
-
- Active Ingredients, Microbial Cleaning Agent
Residues

- swab
-
recovery,

14

Cleaning Validation

(Extraction Efficiency)
(Specificity)
-
swab
- swab
swab

4.7.2. Rinse Sampling

Protocol

-
Swab
-

-
-
(Sensitivity)

-
4.7.3. Solvent Sampling
Rinse Sampling Cleaning
Solution Recovery
Swab

- Recovery
-
15

Cleaning Validation

- Residue
-

- 1

4.7.4. Placebo Sampling

(Placebo) Batch
Placebo Placebo

- Placebo
-

- Recovery
-
Placebo
4.7.5. Direct Surface Monitoring

Bioluminescence Spectrophotometric probe

-
3.8. (Analytical Method)

(Visual Examination)
16

Cleaning Validation

Fluorescence (Dyes)
Complex Methylene Blue
Anionic Detergent Residues Proteins
Specific versus non-specific testing
(Specific testing)

Specific testing
Non-specific testing

Cleaning Validation

Specific Test Method

High Performance Liquid Chromatography (HPLC)
Enzyme Immunosorbant Assay (ELISA)
Atomic Absorption (AA)
Capillary Electrophoresis (CE)

Non-Specific Test Method

Total Organic Carbon (TOC)
pH
Titration
Conductivity
Gravimetric

Non-Specific Testing
Specific Testing
(Sensitivity) (Identification)

Non-Specific Test Method

Surfactants Detergents Specific Test Method

17

Cleaning Validation

4.8.1. pH
: -
(Acid-Base) pH



4.8.2. Conductivity
: (Soluble Inorganic
Materials) pH Probe Unit Conductivity

4.8.3. Total Organic Carbon (TOC)
:
(Organic Materials) Carbon Oxidizing Carbon
Carbon Dioxide
Worst Case Residues Active Ingredients
(Toxic) (Limit)
Limit Specific Testing HPLC
pH Conductivity
TOC Molecular Weight
Validate Validation
Recovery , Linearity, Detection Limit Precision
(Low Level Detection)
4.8.4. Enzymatic (Bioluminescence)
:
Biological Products Proteins Specific Testing
Sensitivity
Proteins Bioluminescence
Validate
4.8.5. Gravimetric Analysis
:
rinse ,
Residues
Recovery

18

Cleaning Validation

4.8.6. Titration : Active Ingredients Cleaning Agents

Titrate

4.8.7. High Performance Liquid Chromatography (HPLC)

:
detector
UV detector specificity

4.8.8. Capillary Electrophoresis (CE) : cleaning
(Biotechnology) Proteins, Amino acid

specificity
4.8.9. Atomic Spectrophotometry : Residue
Inorganic Compounds

(Microbial Contamination)

(Validation of analytical method)

Specific testing

19

Cleaning Validation

Accuracy
Precision
Specificity
Limit of Detection, LOD
Limit of Quantification, LOQ
Linearity
=
o

()

X =

Accuracy: (True
Value) (Reference Standard)

Precision:
(SD)
3-5 (Intra-Day Validation Repeatability)
3-5 (Inter-Day Validation Reproducibility)
Specificity:

Impurities
Degradation Products

Limit of Detection (LOD):

/

Limit of Quantification (LOQ):

20

Cleaning Validation
o

Linearity: Chromatography
(Respond) Plot
Linearity
LOQ Linearity

3.9. (Revalidation)

3.10. (Result and Report)

3 Lots
3.11. (Acceptance Criteria)
Active
ingredients,
3
4.11.1. Visually Clean

Batch

4.11.2. 10 ppm
Limit Test
10 ppm
(Potent Drugs) Hormone
21

Cleaning Validation

4.11.3. 0.1 %
Minimum Daily Dose
Maximum Daily Dose Batch
Safety factor
(Maximum Allowance Residue
,MAR)
Total Residue (TR) MAR
Total Residue MAR
Total Residue = Residues
Residue Swab Rinse Method

Residue Swab = (Amount of Residual Product / Swab) x

Residue Rinse = (Concentration of Residual Product / ) x

Rinse
Residue
Residue Detergent Detergent
Total Residue Active
Ingredient MAR
MAR = (Smallest Therapeutic Dose / 1000) x (Smallest Batch Volume Made / Largest Volume
Single Dose of Other Product Made)
1000 Arbitrary Safety Factor toxicity product
100 Arbitrary Safety Factor toxicity
10,000 Arbitrary Safety Factor toxicity

Organisms 100 CFU/ 25 cm2 ( Swab Test)
Yeast 10 CFU/ 25 cm2
S. aureus, P. aerugenosa, E. Coli Salmonella
Endotoxin Sterile Dosage Forms
22

Cleaning Validation

5. (GLOSSARY)
Automated cleaning :

Bioburden : microbial
contamination ()
Bracketing:



Clean :
Clean in- place (CIP) :

Clean-out- of- place (COP) :

Cleaning agent :
Cleaning validation :

Contaminant :
Dedicated equipment :
Equipment grouping :

Manual cleaning :
Method validation :
Placebo :
Placebo scrubbing (solid washing) : placebo

Revalidation :

23

Cleaning Validation

Residue :
Worst case :
(
)
Validation protocol :
( test parameter )

Validation change control :

24

Cleaning Validation

6. (BIBLIOGRAPHY)
I. Bismuth G. and Neumann S. , Cleaning Validation A Practical Approach, Interpharm Press,
Colorado, 1999.
II. Capote M.J., Documentation for Cleaning Validation : A Protocol Template, Journal of
Validation Technology, 1996.
III. Gavlick W.K., Ohlemeier L.A. and Kaiser H.J., Analytical Strategies for Cleaning Agent
Residue Determination, Pharmaceutical Technology, 1995.
IV. Hall B., Cleaning Validation for The Pharmaceutical Industry , 2000.
V. Institute of Validation Technology, Master Plan for Cleaning Validation ABC Company
Protocol Number: 9501, 1995.
VI. LeBlance D.A., Validated Cleaning Technologies for Pharmaceutical Manufacturing,
Interpharm Press, Colorado, 1999.
VII. PDA Technical Report No. 29, Journal of Pharmaceutical Science and Technology ,
1998.
VIII. , (Cleaning
Validation) , Vol.2 , 2544.
IX. , Method Validation
, 2542.
X. , Validation Part 2: Cleaning
Validation , 2545.

25