Introduction:
Cleaning
validation is the process of assuring that cleaning procedures effectively
remove residue from manufacturing equipment / facilities below a predetermined
level. This is necessary to assure the quality of future products using the
equipment, to cross contamination and as a GMP requirement.
Cleaning
validation has been an area of increased regulatory and industry scrutiny. This
attention is warranted given the increased use of multipurpose equipment and an
overall concern for quality of product. For both industry and FDA inspectors
the concern is the same assurance that equipment is clean and that product
quality and safety are maintained. Cleanings validation provides such
assurance. One of the key component of any cleaning validation strategy are the
analytical method used to measure residuals. The overall is to assure that the
product does not become adulterated from any source whatever; intermediates, excipients
and cleaning reagents must therefore be considered.
Selection of instrument:
Total
Organic Carbon analysis is a new method of analysis applied to a number of
traditional pharmaceutical products in addition to biopharmaceuticals.
The
method offers extremely low detection capability, rapid sample analysis time
and therefore quick turn –around of production equipment and facilities. The method allows the measurements of not
only drug of our interest but also extraneous materials such as process
intermediates, cleaning agents, and protein material not possible by other
method.
The
most significant difference among the analytical methods is in the areas of
cost and detection capabilities. HPLC has the capability for lower detection, but
is also quite costly to use. Spectrometric method (UV) and thin layer
chromatography are lower cost method but at the expense of detection
capability.
TOC
provides a method, which is relatively inexpensive, rapid in analysis time, and
has low detection. Since it detects all carbon residues it can detect
drug,
excipients and cleaning agent residue. Given the rapid analysis time and the
availability of compact system it can be applicable to on line analysis.
HPLC,
TLC or any other specific assay method are unnecessary and added expense in
terms of assay time, cost and downtime. TOC provides an immediate answerer for
validation and for ongoing monitoring at lower cost. It provides assurance that
the surface or rinsate monitored is clean to low residual level.
Selection of Methodology:
There
are 3 methods of Cleaning Validation using TOC Analyzers
1. Rinse Water TOC monitoring.
2. Swab/ Water Extraction/ TOC.
3. Swab/ Direct Combustion/ TOC.
Rinse
Water TOC Monitoring :
*
Broad Spectrum Assay: detects all carbon based residuals.
*
Low Level Detection.
*
Applied to Water soluble or dispersible drugs.
Swab/
Water Extraction/ TOC Method:
*
Easier and Faster than Swab & HPLC Method.
*
Broad Spectrum Assay: detects all carbon based residuals.
*
Low Level Detection.
*
Applied to Water soluble or dispersible drugs.
Swab
/ Direct Combustion / TOC Method:
*
Physical Sampling from the equipment or facility surface
with wetted swabs
*
“The most desirable is the direct method of sampling the
surface of the equipment” from FDA “Guide to
Inspection of Validation of Cleaning Process”
*
Possible to evaluate all kind of drugs including insoluble
drugs,
As
all drugs were water soluble, method for carrying our cleaning validation was
chosen ‘Rinse Water TOC’. Method is simple to use and give an effective picture
of cleaning of the vessel.
Principle
of Measurement of Total Organic Carbon (TOC)
The
Shimadzu Total Organic Carbon Analyzer capable of performing total organic
carbon (TOC), Total carbon Analysis (TC), Inorganic carbon Analysis (IC) and
Non purgeable organic carbon Analysis (NPOC)
1.
Measurement of Total Carbon (TC):
Total
Carbon (TC) is composed of Total Organic Carbon (TOC) and Inorganic Carbon
(IC).
TC
combustion tube is filled with oxidation catalyst and heated to 680 oC. Carrier
gas (high purity air) is supplied into this tube, after it is controlled at a
flow rate
150
ml/min, by a pressure controller and a mass flow controller and moistened by a
humidifier. When sample has been introduced by a sample injector into the TC
combustion tube, TC component in the sample combusted or decomposed to become
CO2. The carrier gas which contains combustion product from the TC combustion
tube flows through an IC reaction vessel and dried by a dehumidifier. It is
then through a halogen scrubber into a sample cell set in a non-dispersive
infrared gas analyzer (NDIR), where CO2 is detected. The NDIR outputs a
detection signal (analog signal), which generates a peak whose area is
calculated by a data processor.
2.
Measurement of Inorganic Carbon (IC)
Sample
is introduced with a sample injector into an IC reactor vessel where carrier
gas is flowing in form of tiny bubbles in the solution acidified by IC reagent.
Only
IC component in the sample is decomposed to become CO2 which is detected by the
NDIR. The IC concentration can be determined in the same procedure as the TC
concentration. Carbon in form of carbonates and hydrogen carbonates can be
measured as IC.
3.
Measurement of Total Organic Carbon (TOC)
TOC
concentration can be obtained by subtracting the IC concentration, from TC
concentration.
4.
Measurement of NPOC (Non- Purgeable Organic Carbon)
TOC
concentration can be obtained in a different procedure if sample has been
acidified before it is set in the equipment. Specifically, the equipment
sparges the
acidified
sample automatically with high purity air to eliminate IC component prior to
measuring TC concentration. The measurement thus obtained is also generally
called TOC, although it is named NPOC here to be distinguished from TOC. NPOC
stands for Non-Purgeable Organic Carbon and refers to non-volatile organic
carbon. It particularly indicates non-volatile organic carbon which will not be
eliminated by evaporation during sparging process; since volatile organic
substance such as organic solvent, which may be contained in sample, is easy to
evaporate at an ordinary temperature, it is possibly eliminated during sparging
process. Organic carbon which is evaporated during sparging process is called
POC (purgeable organic carbon).
Generally,
TOC is measured by following 2 methods:
a) TOC = TC – IC,
b) TOC = NPOC + POC
In
most of the forms of water, POC is considered negligible and TOC is equivalent
to NPOC. All drugs of our interest here are not purgeable organic carbon, hence
we decided to consider TOC = NPOC and only NPOC measurement was carried out.
Computation
of Limits:
Computing
limits for cleaning validation for various drugs involved following steps:
a) Limit for each drug in rinse water was
considered 10 ppm,
b) Sodium Chloride cleaning validation cannot
be carried by TOC and hence was excluded in trial and method development.
c) We converted limit for each drug into
limit for Total Organic Carbon. This was done by multiplying 10 ppm with
molecular weight of carbon and dividing by total molecular weight.
d) In case of drug being mixture of 2
drugs, limit lower of two drugs was taken as TOC limit. For example, Intra
Peritonial is mixture of Dextrose Anhydrous and Sodium Acetate. In that case,
we have considered lower of 2 equivalent TOC values as norm.
Acceptance
Criteria:
Limit
for product in final rinse is 10 ppm.
Details
of Equipment’s:
1. Each drug goes through various tanks
and equipments. Following are details of the equipment required for analysis:
a) One Manufacturing tank ending with ‘A’
for example T01 A,
b) Two Storage tanks ending with ‘B’ for
example T 01B and T 02B,
c) Filling Machine for example BP360,
2. At any given time, 3 drugs are being
manufactured by using 3 tanks & one filling machine for each drug.
Routine
Cleaning Process
1. Tank Cleaning:
Presently for 3 tanks, 3 washes are being
given each by using specific quantity of
water for injection as mentioned in
previous table. Each wash requires spray from all sides to ensure that surface
becomes clean from all sides.
2. Filling machine Cleaning:
Filling machine is being cleaned by spray
of water. In this case, only one wash is
being given.
3. Quality of water used for cleaning:
Water being used for cleaning is Water for
Injection and is extremely pure and is
found to have maximum 150 ppb TOC. Same Water is used as zero water while
carrying out calibration.
Routine
Line Clearance Checking:
For
line clearance of Manufacturing and Storage tanks and Filling machine following
methods are used:
1. Conductivity of rinsing water against
Water For Injection.
2. pH of rinsing water against Water For
Injection.
3. Chemical Identification test.
Instrumental
Conditions of TOC Analyzer
1. Measurement Mode: Non Purgeable Organic
Carbon (NPOC),
2. Calibration using following:
a) Zero Water (Water for Injections having
very small concentration of TOC),
b) Sucrose having Total Carbon
Concentration of 250 ppb, 500 ppb, 750 ppb.
3. Calibration curve was made with above
standards. Linearity of this curve was found to be 0.998.
4. Number of injections was set as best 2
out of 3.
5. Sparge time was set for 1 minute.
6. Acid Ratio: 1%,
7. SD = 0.2
8. CV = 2%
9. In case, concentration values were
found to be higher than 1 ppm, automatic dilution was done to work in the
present range of measurement i.e. 0 to 750 ppb. Whenever, dilution is made,
concentration is corrected
Considering
dilution ratio.
Results
of Cleaning Validation Samples
Calculation
of product traces result from obtained carbon result in ppm
Sample
(Washing –1)
Carbon
found in ppm is
(limit :- ppm)
Mol.
Wt.
Carbon
wt.
Product
traces result = result in ppm x M. Wt.
= ppm
Carbon in product
Sample
(Washing –2)
Carbon
found in ppm is (limit :- ppm)
Mol.
Wt.
Carbon
wt.
Product
traces result = result in ppm x M. Wt.
= ppm
Carbon in product
Sample
(Washing –3)
Carbon
found in ppm is
(limit :- ppm)
Mol.
Wt.
Carbon
wt.
Product
traces result = result in ppm x M. Wt.
= ppm
Carbon in product
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| Cleaning Validation Protocol |
