This document discusses cleaning validation for pharmaceutical manufacturing. It defines validation as providing evidence that a process will consistently produce expected results. Regulations require validating cleaning procedures to confirm effectiveness and reduce residues to acceptable levels. The objective of cleaning validation is to establish reliable cleaning procedures to minimize analytical monitoring. Key principles discussed include establishing a cleaning standard operating procedure considering cleansing agents, equipment, and documentation. Products are grouped based on solubility, potency, and formulation risk factors. Worst case scenarios can be selected either product-specific or equipment-specific.

1. MEDIZEN FOR PHARM. IND.
By Ibrahim Ghareeb
CLEANING VALIDATION
PART 1
1

2. WHAT IS VALIDATION ? The process of providing
documented evidences, that provides a high degree
of assurance that specific process, method, will
consistently produce a result with pre – determined
acceptance criteria.
2

3. 3

4. EFFECTIVENESS OF CLEANING
4

5. REGULATIONS
“Particular attention should be accorded to the
validation of … cleaning procedures” (WHO)
“Cleaning validation should be performed in order to
confirm the effectiveness of a cleaning procedure”
(PIC/S)
“The data should support a conclusion that residues
have been reduced to an ‘acceptable’ level” (FDA)
5

6.  21 CFR 211.65 a)
 Equipment …. surfaces which contact components, in-process
materials, or drug products shall not be reactive, additive or
absorptive…..
 21 CFR 211.67
 Equipment and utensil …. cleaned, maintained, and sanitized at
appropriate intervals to prevent …or contamination that would
alter the safety, identity, strength, quality, or purity ……
 21 CFR 211.182
 Written cleaning Procedure
 Cleaning and use log
 Guidance
 Guide to Inspection for Validation of Cleaning Processes. FDA, 1993
6

7. Objective
 The objective of the Cleaning Validation is the confirmation of a
reliable cleaning procedure so that the analytical monitoring may be
omitted or reduced to a minimum in the routine phase.
SO,
 Cleaning procedures must strictly follow carefully established and
validated methods of execution. This applies equally to the
manufacture of pharmaceutical products and active pharmaceutical
ingredients (APIs). In any case, manufacturing processes have to be
designed and carried out in a way that contamination is reduced to an
acceptable level.
7

8. PRINCIPLES
CLEANING SOP
PRODUCT GROUPING
WORST CASE SELECTION
SETTING ACCEPTANCE CRITERIA
SAMPLING METHODS
8

9. CLEANING SOP
TWO CONSIDERATION ARE TAKEN:
1- CLEANSING AGENT
Chemistry,temperature and time
2- EQUIPMENT
Mechanics and cleaning tools
9

10. CLEANSING AGENT
10

11. 1- Chemistry
- Solubility of both excipients and API.
- Detrmining solubility of API in different PHs.
2- Temperature
-Accelerating agent and for microbial aspect
-Assuring the temperature constancy
-Assuring the temperature control
11

12. 3- Time
-Minimizing the time required to take effect using
optimum arrangement of chemical, temperature and
mechanical factors
Critical inspection of working procedures within the
total process (pre-cleaning,assembly/disassembly,
rinsing, drying)
12

13. EQUIPMENT
1- Mechanics:
-Type of cleaning:CIP,COP and manual
- Difficult to clean locations in equipment should be
determined that they will be sampling location
during CV.
13

14. 2- Selection of suitable tools (e.g. sponges, brushes,
high-pressure cleaners) while considering material
and surface compatibility.
Conditions
Do not produce fibers.
Disposable as possible.
14

15. Once all the details of the cleaning procedure have
been firmly established, a written cleaning
instruction (SOP) has to be established.
15

16. The following specifications must be contained in SOP:
 Cleansing agents and concentration of the cleaning
solution
 Quantity and temperature of the cleaning solution
 Mechanics(non accessible areas)
 Cleaning time and cleaning cycles
 Rinsing and secondary treatment
 Assembly and disassembly procedures required for
cleaning
16

17. PRODUCT GROUPING
Bracketing(grouping)
"Cleaning procedures for products and processes which are
very similar, do not need to be individually validated. It is
considered acceptable to select a representative range of
similar products and processes concerned and to justify a
validation programme which addresses the critical issues
relating to the selected products and processes. A single
validation study under consideration of the `worst case' can
then be carried out which takes account of the relevant
criteria. This practice is termed `Bracketing'." (PIC/S
PI006)
17

18. Bracketing for products:
According to risk groups that are:
-Risk factor "solubility" :The product contains a poorly
soluble active pharmaceutical ingredient.
-Risk factor “Potency“: The product contains a highly potent
active pharmaceutical ingredient(lowest API conc./dose).
-Risk factor "formulation”:The product contains
formulation components that are difficult to remove, such
as grease matrices, dyes or flavors.
18

19. CASE STUDY
19

20. 20

21. 21

22. 22

23. WORST CASE SELECTION
Two possible approaches
 product-specific implementation
 equipment-specific implementation
23

24. For the product-specific approach, a validation
protocol is compiled for every critical product that
includes all types of equipment necessary for the
production process.
24

25. For the equipment-specific approach, a validation
protocol is compiled that includes all critical
products manufactured on this equipment.
25

26. 26