2. What is cleaning validation?
Cleaning validation is documented evidence that the
cleaning process can effectively and reproducibility
clean equipment to a pre-defined acceptable level.
Pre defined Acceptable level ?
MACO : Maximum Allowable Carry Over
Microbial Limit
Cleaning Attributes: pH, TOC, Conductivity
3. RATIONALE
Effective cleaning prevents unacceptable levels of
contamination from products, cleaning agents
A systematic, standardised approach to cleaning
validation and verification is required in order to
provide assurance that cleaning is effective.
4. Objective:
The objective of cleaning validation is:
To verify the effectiveness of the cleaning procedure that
the equipment is consistently cleaned of product,
detergent and microbial residues to an acceptable level,
to prevent possible contamination and cross-
contamination.
To provide documented evidence that an approved
cleaning procedure will provide clean equipment, suitable
for its intended use.
5. Cleaning Validation Approach:
The approach for conducting cleaning validation studies is
“Risk based” approach i.e. to select “worst case” on the
basis of following criteria:
Solubility.
Ease of Cleaning.
Toxicity.
Potency.
6. CALCULATION OF ACCEPTANCE
CRITERIA
There are different methods for calculation of
Acceptance criteria for cleaning validation study which
are as follows:
Based on Therapeutic Daily Dose
Based on 10 ppm General Limit
Note: Both methods are used for calculation and most
stringiest limit calculated from two methods will be
used for cleaning validation study.
7. FORMULA USED FOR CALCULATION
1/1000 of Therapeutic daily dose:
MACO = TDD previous (mg) x BS (mg)
1000 x TDD next (mg)
Where:
MACO = Maximum Allowable Carryover
TDD previous = Minimum TDD of the contaminating substance (mg)
TDD next = Maximum TDD of the contaminated substance (mg)
BS = Batch size of the contaminated substance (mg)
1000 = Safety factor
10 ppm general limit:
MACOppm = MAXCONC x MBS
MACOppm Maximum Allowable Carryover: acceptable transferred amount
from the investigated product ("previous"). Calculated from general ppm limit.
MAXCONC General limit for maximum allowed concentration (kg/kg or ppm)
of "previous" substance in the next batch.
MBS Minimum batch size for the next product
11. Question
Product D is considered as investigated Product whose
therapeutic daily dose is 5 mg/day. The next Product
which will be manufactured is Product B which have a
batch size of 417.749 kg i.e. 417749000 mg and its
therapeutic daily dose in 25 mg/day. Calculate the
MACO based on both methods i.e. therapeutic
approach and 10 ppm (0.00001 mg) general limit.
Which limit will be used as MACO.
12. Answer
Based on therapeutic approach
MACO = TDD previous (mg) x BS (mg)
1000 (safety factor) x TDD next (mg)
= 5x417749000
1000x25
= 83549.8 mg
13. Answer
Based on 10 ppm general limit
10 ppm general limit:
MACO = MAXCONC x MBS
= 0.00001x417749000
= 4177.49 mg
14. ANSWER
10 ppm general limit will be considered MACO
due to most stringent limit calculated.
15. RECOVERY STUDY
Recovery factors for cleaning validation residue testing
are an essential element of any cleaning validation
program. The FDA Guide to Inspection of Validation
of Cleaning Processes states that firms need to “show
that contaminants can be recovered from the
equipment surface and at what level”. The Health
Canada and the Pharmaceutical Inspection
Convention and Pharmaceutical Inspection Co-
operation Scheme (PIC/S) cleaning validation
guidances also require that recovery experiments be
completed. Recoveries are necessary for direct surface
sampling using a swab.
16. RECOVERY STUDY
To determine the recovery factor through experiments
in which sample equipment materials of construction
(MOC) spiked with known amounts of the substance
of interest are recovered and tested. The recovery must
be capable of capturing a sufficient amount of material
to allow an accurate and precise measurement of the
spiked component.
17. Recovery studies
Usually carried out in the laboratory using coupons to
simulate the product contact surface.
•Generally 80% recovery
required/ considered good
•Less than 50% recovery
needs a justification / not
acceptable
18. Recovery Factor:-
% Recovery = Area of Sample × Concentration of Standard ×100
Area of Standard × Concentration of Sample
Acceptance Criteria for recovery
>80% Considered good
>50% Reasonable
<50% Questionable
19. Sampling Method:
Two methods of sampling considered to be acceptable. These are
direct surface sampling and rinse sample. A combination of the two
methods is generally the most desirable and best suited. Selection of
method shall be identified and justified in the protocol.
a) Surface Sampling (Direct Method):
This method is designed for sampling of hard to clean area i.e.
surface of Equipment, Machine area etc. Swab of hard to clean
areas shall be taken by dragging it on the surface of the equipment
horizontally and vertically. Press down the swab handle firmly to
ensure proper surface contact Swab Samples will be taken & should
be covered 10cm x 10cm for QC testing & 5cm x 5cm area for
Microbial tests. Swab will be taken in right to left and top to bottom &
vice versa directions,
20. Continue….
b) Rinse Sample (Indirect Method):
This method allows sampling of a large surface area
that are inaccessible or that cannot be routinely
disassembled and provides an overall picture. Rinse
samples may give sufficient evidence of adequate
cleaning where accessibility of equipment parts can
preclude direct surface sampling, and be useful for
checking of the residues for cleaning agent e.g.
detergents.
21. SAMPLING METHODOLOGY
The recommended strategy is to wet a swab with
solvent. Remove any excess solvent from the swab as
described previously. Swab an area of 100 cm2 (10 cm x
10 cm).
22. EQUIPMENT HOLD TIME
Dirty Hold Time
Definition: The interval allowed between the
completion of production activities and the start of
cleaning
Purpose: The dirty hold time validation demonstrates
the capability of the cleaning cycle to reduce
bioburden and endotoxin to the acceptance criteria.
23. EQUIPMENT HOLD TIME
Clean Hold Time
Definition: The interval that equipment may be held
between the completion of cleaning and the initiation
of the subsequent manufacturing operation without
requiring further cleaning
Purpose: The purpose of validating a clean hold time
is to confirm that the equipment remains clean
following cleaning and before use when stored under
normal storage conditions.
24. CLEANING PROCESS PARAMETERS
Cleaning process parameters typically used during cleaning
validation mentioned below:
Cleaning time
Cleaning technique (Automatic/Manual Cleaning)
Quantity of Water used
Quantity of cleaning agent used
Temperature of Water
Clean Hold time
Dirty Hold time
25. ROUTINE MONITORING
To ensure the continued effectiveness of the cleaning
cycle, routine monitoring/trending is required for
validated cleaning processes. Depending upon the
facility and products, this includes testing and
monitoring of critical cleaning attributes (TOC,pH,
conductivity, Bioburden, endotoxin)
26. REFERENCES
WHO Guideline (Appendix -3 Cleaning Validation)-
TRS 937, 2006
(APIC). Sep-2016
Section 211.67 of part 21 of the Code of Federal
Regulations (CFR)
Section 211.182 of part 21 of the CFR
Health Canada Cleaning Validation Guidelines
(GUIDE-0028)
PIC/S Annex15 Qualification and validation PE 009-
14 July 2018
