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CLEANING VALIDATION

Research · April 2015

DOI: 10.13140/RG.2.1.4237.9688

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CLEANING VALIDATION

1
 WHO validation definition
The documented act of proving that any
procedure, process, equipment, material,
activity, or system actually leads to the expected
results.
 WHO validation definition
continue

Qualification or validation?

A system must be qualified to operate in a

validated process
Qualify a system and/or equipment
Validate a process
Qualification versus validation, e.g. you
qualify an autoclave, whereas you validate
a sterilization process
• DOCUMENTATION
• VMP
• General procedure for cleaning validation
• Cleaning validation protocol
• Cleaning procedures
• Sampling & Testing
• Methods of analysis for active pharmaceutical
• ingredient, detergents, solvent residues
• Test method validation protocol
• Microbial contamination assay procedures
• Sampling procedures
• Report

4
 RESIDUE/CONTAMINATION TYPES

• Viable  Non-Viable Particulate

Microorganisms  API
– Bacteria  Excepient
• Gram Positive
 Dirt,silica
• Gram Negative
– Molds, Fungus  rubber, teflon ,

– Virus? gasketing,elastomers
 Metal, rust,
 graphite
 CONTAMINATION TYPES (cont.)

• Non-Viable Chemical (thin films or invisible)

– endotoxin
– drug actives
– biologically active materials
– excipients and inerts
– lubricants, sealants
– cleaning agents, disinfectants, sterilant residues
– water impurities
 CONTAMINATION SOURCES
Microbial, Particulate and Chemical

• INDIRECT • DIRECT
– Workers – Workers
– Air – Air
Product

– Environmental – Components
surfaces – Product contact
– Process surfaces
Equipment
Objective Prevent <<cross contamination>>
• Contamination in product is lower than a
pre‐established (pre‐determined)limit
• The pre‐established limit must guarantee:
- Absence of pharmacological effect due to the
residue of API from the product
‐ Or absence of toxic effect (API, cleaning agent,
bacteria, endotoxins,…)

8
 Cleaning validation protocol (1)

• Description of the cleaning procedure

+diagram +definition of the critical parameters
• Definition of the maximum hold time
of<<dirty>> and maximum hold time
of<<clean>>equipment to be tested
• List of Logbooks, Records and Cleaning
Procedures

9
 Cleaning validation protocol (2)

• Definition of the study: list all materials

concerned, sampling plan, sample types,
sampling procedures, number of repetitions
• Acceptance criteria: the choice and
calculation must be described and justified

10
 Cleaning procedure
• Must be tested (i.e. result of development and
experience)
• Written and approved
• Precise
• Including the Critical cleaning Process
Parameters (CCPs) that can be measured and
monitored (e.g. temperature, time,
concentration, volumes,)
• Log book or document for recording.
11
Remarks!!!!!(1)
• No cleaning validation without written
cleaning procedures
• Re‐validation in case of change in the
cleaning procedure (change control)
• Change in a critical parameter such as Time,
Temperature, detergent, volume,…
• Recording of the cleaning operations routinely

12
Remarks!!!!(2)….be process oriented
• Several cleaning procedures for the same
equipment in function of different products =
validation of each procedure.
• It is a validation of the cleaning
procedure and not of the products!!!!
• The conclusion of the validation report
must include the references of the
validated cleaning procedures

13
Personnel
• Trained on the cleaning procedure.
• Recording in the appropriate log book or
document for cleaning.
• Any deviation in the cleaning procedure must
be notified and recorded.

14
Detergent, disinfectant
• Approved reference
• Quality control at receipt
• Storage, conservation
• Limit date of use after opening
• Respect of concentrations, dilutions
• Any deviation must be registered
• Reference, batch number, limit date of use
after
• opening must be recorded in the log book.

15
Analytical methods(1)
• Translate the residue limit values (μg/cm2)
• into μg/ml taking into consideration:
• the smallest surface sampled
• the volume of solvent used to dissolve the
residue present in the swab.
• This concentration (μg/ml) must be
quantifiable by the test method.

16
Analytical methods(2)

• Sensitive :can detect the limit values of the residues

tested for
• Validated: (LOD, LOQ, linearity, recovery)
• Determine the percent recovery for each surface
material (e.g.: SS, silicon, polypropylene)
• The acceptance criteria :≥ 70 % (Exceptions must be
justified)

17
Sampling
• The sampling techniques must be written and
approved.
• Swabbing non sterile/sterile (PC/Micro)
• Rinse water (PC/Micro)
• Contact Plates (Micro)

18
Swabbing
• Appropriate materials (e.g. Texwipe® swabs)
• Decontamination (of the sampling utensils –
swabs – etc..)
• Training of the Samplers
• Include a blank analysis in parallel with the
analysis of the swab samples

19
Walsh case Swab Procedure
 What kind of swab?

• Material of construction-
– cotton
– polyester
– polyurethane
– other

Affects absorbency, shedding, selective adsorption and

release; interference
Rinse water

• To know : the total surface of the equipment to be

rinsed
• To know : the volume of the rinse
-Calculate the final concentration in the rinse water of
the residue present considering the limit value on
the equipment ≥ LOQ of the method

22
 Recovery of Insolubles in Water

Active Actual (as TOC) Recovery Recovery

Solubility (HPLC) (TOC)
Miconazole nitrate 160 ppm 83 ppm 5.2% 20.8%
Recovery from coupons @ 4g/cm2 level
(~2 ppm TOC in 20 mL low TOC Water)
 Recovery of Insolubles in Water

Active Actual (as TOC) Recovery Recovery

Solubility (HPLC) (TOC)
Miconazole nitrate 160 ppm 83 ppm 97.0% 95.4%
Recovery from coupons @ 4g/cm2 level
(~2 ppm TOC in 20 mL 0.1N H3PO4 in low TOC water)
 Sample Locations:

• poorly drained surfaces

• poorly sprayed surfaces
• low flow areas of piping, valves, ports, etc.,
• baffle back sides
• under impellers
 Hot Spots and Critical Spots

• Hot Spots
– Areas that are slower or harder to clean and
consistently tend to have more residue
• Critical Spot
– Areas where any remaining residue is likely to be
transferred and will pose a high risk of being
concentrated in one or several dosage units rather
than being dispersed and diluted into the next
batch.
 Converting Limits to Acceptance
Criteria, for two product system
 400 mg or 2 g MAC
 Equipment surface limit 400mg/14,000 =
SA= 14,000 cm2
29 mcg/cm2
2 g/ 14,000= 143 mcg/cm2
 Sample acceptance criteria Surface Limit (29
A
mcg/cm2) X area sampled( 25 cm2)
5cm x 5 cm batch B
= 725 mcg, 3.6 mg
 Sample acceptance criteria
ppm = swab limit/sample vol (40 ml) A
= 725mcg/40ml=18 ppm; 90 ppm A
A
 Batch Rinse
Sampling
MAC 400 mg

Total Rinse AC
MAC Volume ppm
400 mg 1000 L 0.4 ppm

400 mg 100 L 4 ppm

2g 1000 L 2 ppm MAC / L rinse

400 mg/1000 L= 0.4 ppm
400 mg/ 100L = 4 ppm
2g 100 L 20 ppm
 Rinse water: example of calculation of the rinse water
quantity
• LOQ of the method: 0.5μg/ml
• Limit value calculated: 2μg/cm2
• Surface of the transfer tube : 200 cm2
• Percent recovery on the material for the transfer
tube : 80%
• Maximum quantity of rinse to be applied on the
tube to be sure that we will obtain a quantifiable
concentration in case of failure of the
cleaning=(200×2×0.8) / 0.5=640ml

29
 Equipment hold time

• Validate the maximum dirty equipment hold

time before cleaning …what do you think?

• Validate the maximum clean equipment hold

time after cleaning and before using it… what
do you think?

30
Scope of the validation
• Visible residues
• Non visible chemical residues
• Active pharmaceutical ingredient (API)
• Degradation products
• Preservatives
• Detergents
• Disinfectants
• Microbial contamination

31
Possible principles

• Validation of the cleaning procedure after each

manufactured product
• Validation of the cleaning procedure after the Worst
Case manufactured product, incombination with the
following criteria:
‐Physical (cleanability)
‐Chemical (solubility)
‐Pharmacological
‐Toxicity (DL50/NOEL)

32
Validation principle
• Demonstrate that the results of 3 consecutive
cleaning validations of the same product are
satisfying
• interest of choosing the<< worst case>>
product

33
 “Grouping” or “matrix “ approach is
acceptable?
• FDA Q7A
– Validation of cleaning procedures should reflect
actual equipment usage patterns. If various APIs
or intermediates are manufactured in the same
equipment and the equipment is cleaned by the
same process, a representative intermediate or
API can be selected for cleaning validation. This
selection should be based on the solubility and
difficulty of cleaning and the calculation of
residue limits based on potency, toxicity, and
stability.
Worst case
Determination of the<<worst case>>product

Matrix approach

36
 How to determine worst case
Methodology(1)
• List the products into groups according to the
pharmaceutical form and the equipments
needing cleaning validation
• Attribute a score for the cleanability,
solubility , Toxcity, Potency,…of the product
tested (in general the API)

37
 Evaluation per Q7A
A B C D E
Product Type
Solubility
“Cleanability”
Potency
Toxicity
Stability

Does Solubility Index predict relative residue removal rate?

Solubility & cleanability
Drug potency
Drug Toxicity
 Limitation of the <<worst case>>option(1)
• If the worst case does not allow the cleaning
validation of all the production equipments,
then the equipments not used in the
manufacture of the worst case must be
validated with another product

42
 Limitation of the<< worst case>>option(2)
• If the worst case is not the first product manufactured:
‐Verify the effectiveness of the cleaning
procedure after each product
‐An identical protocol to that of the worst
case validation protocol but only one
cleaning validation run for each product
‐Several validated analytical methods are
needed (one for each API)

43
Important remark!!!!
• Reminder GMP appendix 15:<<test until
clean>>is not considered an appropriate
alternative (to cleaning validation)

44
 Implication of then<<worst case>>option
• Introduction of a new product in manufacturing
• ‐Change control evaluate the validity of the
cleaning validation done and confirm that the
newly introduced product does not constitute a
new worst case and does not impact the previous
validation
• Matrix evaluation for decision:‐
‐Validation is still valid: new product is not “Worst Case”
‐Or validation must be repeated with the new product becoming
the <<worst case>>

45
 How to determine worst case
Methodology(2)
• Calculate the acceptable quantity of the API
tested which could be transferred to a unit of
the next batch without causing a risk or
undesirable effect to the patient (e.g.. without
therapeutic , pharmacological, or toxic
effect)=MACO determined generally in mg
‐Attribute a score for the MACO

46
 Calculation of the MACO
(Maximum Allowable Carry Over)

• MACO=(TD minA × BS minB) / (SF × TDD maxB)

• TD minA: Minimum therapeutic dose of the active ingredient
of the product A expressed in mg.
• BS minB : Minimum batch size of the product B (the next
product which could be contaminated by the previous
product A) in number of unit doses (or in mass/volume)
• TDD maxB: Maximum therapeutic daily dose of the product B
expressed in units of doses (or in mass /volume of the unit
dose ,as in BS minB)
• SF: Safety factor: 100 for topic form,1000 for oral dosage
form,10000 for parenteral dosage form

47
 The worst case of the (MACO)
• The worst case of the<< MACO >>is the
product with the lowest residue result.
• To calculate, the safety factor being constant,
we must determine which case will be the
most unfavorable for product B => the lowest
ratio BSmin / TDDmax

48
Remarks!!!!(1)
• It is important to be consistent in the units:
If we use the mass instead of the number of
dose units for B, the BS minB must be expressed in mg
if the TDD maxB is expressed in mg.
• The TDD maxB expressed in mass
corresponds to a multiple of the mass of the dose unit
and not the content of API in the dose unit

49
Remarks!!!!(2)
• The MACO must be calculated for all the products
e.g. each product is considered to be product A
• The minimum batch size B = the minimum industrial
validated batch size
• So calculate for each product the ratio: BSmin /
TDDmax and then choose as <<product B>>the
product with the lowest ratio
• Then calculate the MACO for each product using the
lowest ratio: e.g. which will give the lowest MACO

50
Example :Calculation of MACO

51
Details of calculation

52
 Scoring
• Solubility and cleanability: in general attribute scores
from 1 to 4 in ascending order of difficulty to dissolve
& difficulty to clean
• MACO: in general attribute scores from 1 to 4 in
descending order from the highest to the lowest
MACO with a factor of 10 Example:
‐MACO : 1 to 9 mg :score: 4
‐MACO :10 to 99 mg : score :3
‐MACO :100 to 999 mg : score : 2
‐MACO :> 1000 mg : score :1

53
Choice of the <<worst case>>
• The worst case = the highest result of the
multiple of the 3 scores:
‐ cleanability x solubility x MACO

54
Matrix example

55
Conclusion example
• The cleaning procedures of equipments 2,
3,4,5 can be validated with the product B

• The cleaning procedure of the equipment 1

can be validated with the product E

56
 Active pharmaceutical ingredient residue

Calculation of the limit value for the validation

57
Calculation of the maximum acceptable value of
residue

• Calculate the surfaces of equipments

• Determine for each product the surface of
equipments in common with the equipments
used in the manufacture of the product A
<<worst case>>

58
Setting limits
• Regulatory authorities do not set limits for specific products
• Logically based
• Limits must be practical, achievable and verifiable
• Allergenic and potent substances
• Limit setting approach needed
• Uniform distribution of contaminants not guaranteed
• Decomposition products to be checked
• Setting limits; cleaning criteria:
– visually clean
– 10ppm in another product
– 0.1% of therapeutic dose

59
 Validation
Setting limits: “Visually clean”
• Always first criteria
• Can be very sensitive but needs verification
• Use between same product batches of same
formulation
• Illuminate surface
• Spiking studies

60
 Yet, the US Food and Drug Administration's Guide to Inspection of
Validation of Cleaning Processes and other literature discount using a
visible limit as the sole acceptance criterion for cleanliness.
Conversely, Mendenhall concluded that visible cleanliness criteria
were more rigid than quantitative calculations and are clearly
adequate for determining cleanliness.
Other recent articles describe the justification and application of a
visible-residue limit (VRL). Many research teams have established
quantitative VRL levels. Fourman and Mullen determined a visible
limit of ~100 μg per 2 X 2-in. swab area or ~4 μg/cm2 . Jenkins and
Vanderwielen observed residues as low as 1.0 μg/cm2 with a light
source. Forsyth et al. determined <0.4- to >10-μg/cm2 VRLs for active
pharmaceutical ingredients (APIs) and excipients.

“Application of Visible-Residue Limit for Cleaning Validation”, Richard J. Forsyth and

Vincent Van Nostrand ,Oct 2, 2005 Pharmaceutical Technology
 1.7 g/cm2
6.9 g/cm2
17.2 g/cm2

13.7 g/cm2 3.4 g/cm2

17.2 g/cm2 0 g/cm2
“Application of Visible-Residue Limit for Cleaning Validation”, Richard J. Forsyth and Vincent
Van Nostrand ,Oct 2, 2005 Pharmaceutical Technology
Criteria
• 4μg/cm2 is compatible with what can be seen
with the naked eye:
‐Color
‐Powder
‐Ruggedness
‐Stain
‐Film

64
 Tools
• Naked eye
• Torch
• Mirror
• Surface Light

65
WHERE
Areas difficult to clean:
‐Connections
‐Seals
‐Agitator rotors
‐…..

66
 Validation
Setting limits: “10ppm”
• Historical
• In some poisons regulations
• Pharmacopoeias limit test
• Assumes residue to be harmful as heavy metal
• Useful for materials for which no available
toxicological data
• Not for pharmacologically potent material

67
 Validation
Setting limits: not more than 0.1%
• Proportion of MINIMUM daily dose of current
product carried over into MAXIMUM daily dose of
subsequent product
• Need to identify worst case
• ≤ MACO/surface of equipment in common

68
Acceptance criteria of the limit value in μg/cm2
• The criterion of choice will be the lowest of the 3
following acceptance criteria
• ≤ 10 ppm of the API of product A in the finished
product B expressed in μg/cm2 =(10 x BS in
gram)/surface of equipments in common
• ≤ 4 μg / cm2 of API of product A on the surface of
the equipment ( = the theoretical limit of “visible
clean”)
• ≤ MACO/surface of equipment in common

69
 Limit acceptable residue for the
Validation

• The residue level which will be considered as

limit is the lowest result of the three options

70
 Conclusion of example (1)

• The limit value applicable for the cleaning

validation of equipments 2,3,4,5 is 0.8
μg/cm2

71
 Detergent

• Determination in the rinse water:

conductivity, TOC, pH

72
Microbiology

73
Acceptance criteria after cleaning
• Rinse water : specification of purified water ≤ 20
CFU/ml (non sterile)
≤ 1 CFU/ml (sterile)
• Contact Plates : ≤ 40 CFU /25cm2
(non sterile)
• Swabs: ≤ 40 CFU / swab (non sterile)
≤ 1 CFU / swab (sterile)
• Absence of specified microorganisms: like Coliforms,
P.aeruginosa, Burkholderia cepacia, Yeasts, Fungi

74
 Acceptance criteria after hold time clean
equipment
• Contact Plates : ≤ 40 CFU /25cm2
(non sterile)
• Swabs: ≤ 40 CFU / swab (non sterile)
≤ 1 CFU / swab (sterile)
• Absence of specified microorganisms: like
Coliforms, P.aeruginosa, Burkholderia cepacia,
Yeasts, Fungi

75
Report
• Results
• Discussions
• Deviations
• Conclusion

76
Post Validation Monitoring
• Program includes review of the cleaning
Records
• Periodic control (e.g.: samples+ specific or
non specific control)
• Evaluation of the impact of the introduction
of a new product
• Change control

77
• Very Useful Link on PIC/S :
http://www.picscheme.org/links.php

Navigate to:

FDA, BP, USP, WHO, PIC/S, ICH, EMEA, EP,

ECA,…..

78
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