Cleaning Validation
-
Upload
vipinchaudhary -
Category
Documents
-
view
186 -
download
27
Transcript of Cleaning Validation
1
A PRACTICAL APPROACH FOR
CLEANING VALIDATION
2
Excerpts from guidelines - Objective
• To avoid contamination of the following pharmaceutical product in the subsequently manufactured products.
3
Excerpts from guidelines - Objective
• To design and carry cleaning in a way that contamination is reduced to an acceptable level.
4
Excerpts from guidelines - Objective
• To have a documented evidence that an approved cleaning procedure will provide ‘clean’ equipment.
5
Excerpts from guidelines - Objective
• To confirm a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.
6
Acceptance criteria - Principles
• The limits should be practical, achievable and verifiable.
• Grouping:• Product specific Cleaning Validation for all
products,• Grouping into product families and choosing
a "worst case" product,• Grouping into groups of risk (e.g. very soluble
products, similar potency, highly toxic products, difficult to detect).
7
Acceptance criteria
Carry-over of product residues should meet defined criteria, for example the most stringent of the following two criteria:
Chemical• No more than 0.1% of the normal therapeutic dose
of any product will appear in the maximum daily dose of the following product,
• No more than 10 ppm of any product will appear in another product,
Visual• No quantity of residue should be visible on the
equipment after cleaning procedures are performed.
8
Acceptance criteria
Microbiological limit for oral solid dosage form
Total aerobic microbial count - NMT 1000 cfu/g
Total combined Yeast and mold count - NMT 100 cfu/g
Absence of USP indicator organisms i.e. - E.coli- S. aureus- Salmonella species
9
Grouping (Bracketing)
• Equipment usage• Solubility• Therapeutic activity
10
Method Validation
MethodValidation
Accuracy
Precision
Limit of Detection
Limit of Quantitation
Linearity
Specificity/Selectivity
Ruggedness/Robustness
11
Accuracy
• Accuracy is the measure of exactness of an analytical method, or the closeness of agreement between the measured value and the value that is accepted as a conventional true value or an accepted reference value
12
Precision
• The Precision of a method is the degree of agreement among individual test results, when the procedure is applied repeatedly to multiple samplings of a homogeneous sample
13
Limit of Detection
The lowest amount of analyte in a sample which can be detected but not quantitated as an exact value.
(The Limit of Detection is mostly a parameter of limit tests)
14
Limit of Quantitation
The lowest amount of analyte in a sample which can be quantitatively determined with defined precision and accuracy under the stated experimental conditions.
15
Specificity/Selectivity
The Specificity of a method defines the ability of the method to measure the analyte of interest to the exclusion of other relevant components.
Selectivity describes the ability of an analytical method to differentiate various substances in a sample.
16
Linearity
• The linearity of a method is its ability to elicit results that are directly, or by a well defined mathematical transformation, proportional to the concentration of analyte in the sample
17
Ruggedness / Robustness
• Ruggedness is the of reproducibility of the test results obtained for identical samples under normal (but variable) test conditions.
• The Robustness of a procedure is a measure of its capacity to remain unaffected by small but deliberate variations in the method parameters and provides an indication of its reliability in normal usage.
18
Stability
• Stability of swab solvent / rinse solvent
The stability of swab solvent or rinse solvent should be established (during its hold period) to prove that once swab/rinse is collected the active is stable till end of the analysis
19
Recovery
• Recovery by swab / rinse
The recovery of active by swab/rinse method should be established (Generally accepted minimum recovery is 50%), and corrective factor should be considered for every result.
20
Cleaning validation approach for Solid Dosage form
(Swab method)
21
Formulae
• 10 ppm Criteria
Milligrams of active ingredient in product A permitted/4 in.2 swab area =
R x S x UT
whereR = 10 mg active ingredient in product A/kg of product B.S = Batch size in kilograms of product B.U = 4 in.2/swab. (Swab surface area)T = equipment surface area in common between products A and B
expressed as square inches.
22
Formulae
• Dose criteriaMilligrams of active ingredient in product A permitted/4 in.2 swab area =
I x K x M
J x L
where
I = 0.001 x minimum daily dose of product A
K = number of dosage units per batch of final mixture of product B.
M = 4 in.2/swab.
J = maximum number of dosage units of product B taken/day.
L = equipment surface area in common between products A and B expressed as square inches.
23
Data Collection
Batch sizes (in Kg) of all products Batch sizes (in number of dosage units) of all products Minimum daily dose of all products Maximum daily dose of all products Common surface area between all the products
Equipment list used for all the products Equipment details with design Calculation of contact surface area of all equipment Matrix for common equipment between two products
24
Equipment usage matrix - A Glimpse
25
Equipment usage matrix - A Glimpse
Octagonal blender
26
Equipment usage matrix - A Glimpse
27
Equipment usage matrix - A Glimpse
28
Equipment usage matrix - A Glimpse
29
Equipment usage matrix - A Glimpse
Common surface area
30
Equipment usage matrix - A Glimpse
Table of product to product common surface area
31
Equipment usage matrix - A Glimpse
Table of Acceptance criteria by 10 ppm criteria
Minimum acceptance by 10 ppm = R x S x U = 10 x 5.75 x 4 = 0.019 mg/swab T 11827.6
32
Equipment usage matrix - A Glimpse
Table of Acceptance criteria by Dose criteria
Minimum acceptance by Dose criteria = 0.001 x K x M = 0.001 x 10 x 25000 x 4 = 0.021 mg/swab J x L 4 x 11827.6
33
Equipment usage matrix - A GlimpseTable of product to product common surface area
34
Dirty Equipment Hold Time (DEHT)
The time from the end of manufacturing until the beginning of the cleaning process is called dirty Equipment Hold Time (DEHT)
Effects of DEHT:1. Drying of dirt on surface of equipment2. Microbial proliferation3. Difficult removal of contaminant
Generally accepted DEHT is 12 or 24 hours, where critical it shall be validated.
35
Clean Equipment Hold Time (CEHT)
The time from the end of the cleaning process until the beginning of the use of the cleaned equipment for manufacture of the next product (CEHT)
Effects of CEHT:1. Any equipment cannot stay ‘clean’ for longer
durations2. The microbial proliferation from a source already
present on surface3. External contamination of microorganism4. External contamination of other chemical entities
Generally accepted CEHT is 24 to 72 hours, where ever critical it shall be validated.
36
Equipment cleaning Validation Protocol
• Basis of protocol design– Equipment specific– Product specific
37
Equipment cleaning Validation ProtocolWhat protocol shall address:o The objective of the validation processo Responsibilities for performing and approving the
validation studyo Description of the equipment to be usedo The interval between the end of production and the
beginning of the cleaning procedureso Cleaning procedures to be used for each product, each
manufacturing system or each piece of equipmento The number of cleaning cycles to be performed
consecutively,o Any routine monitoring requirement
38
Equipment cleaning Validation Protocol
What protocol shall address:
o Sampling procedures, including the rationale for why a certain sampling method is used,
o Clearly defined sampling locations o Data on recovery studies where appropriateo Analytical methods including the limit of detection and
the limit of quantitation of those methodso The acceptance criteria, including the rationale for
setting the specific limitso Other products, processes, and equipment for which the
planned validation is valid according to a “bracketing” concept
o When Re-validation will be required.
39
Equipment cleaning Validation Protocol
What parameters shall be studied during cleaning process
At what point does a piece of equipment become clean?What does visually clean mean?Does the equipment need to be scrubbed by hand?What is the most appropriate solvent or detergent?What is the temperature of solvent used?What quantity of solvent is used for cleaning?Are different cleaning processes required for different products in contact with a piece of equipment?How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?
40
Summary
Product details Method ValidationEquipment Details
•Grouping•Matrix •Acceptance criteria
Protocol designing
Execution of cleaning validation
(3 consecutive runs)
Cleaning validation report
Re-validation
41
Thank you