Tutorial
Q.1What are considered as being acceptable limits for
cross-contamination when performing cleaning validationThere are a
number of options available when determining acceptance
criteria.
A. Limiting the level based on toxicity dataAn Acceptable Daily
Intake (ADI) is calculated with suitable safety factors applied and
this is converted to the maximum allowablecarryover to the API.
B. Pharmacological Dose Method:
The philosophy is to reduce the levels of residual product in
each piece of equipment, such that no greater than 1/1000 of the
normal therapeutic dose will be present per typical dose of the
next product to be run in the equipment. The validation protocol
should include a calculation, which ties this philosophy to the
acceptance criteria for thesamples to be tested.
C. Limiting the level of product which could appear in the
following products.
Limits from 10ppm up to 0.1% (based on the ICH impurity document
which indicates that up to 0.1% of an individual unknown or 0.5%
total uknowns material may be present in the product being tested
)
Q 2 Can the sampling for the microbial monitoring of air in
non-sterile areas where susceptible products are produced be
conducted when there are no manufacturing packaging activities.A.
The sampling should occur during actual manufacturing or packaging
in order to reflect the conditions to which the products being
produced are really exposed. Monitoring between production runs is
also advisable in order to detect potential problems before they
arise.
Q 3 When should a company validate/ revalidate cleaning
procedures? Whenis validation not required. 1. Normally only
cleaning procedures for product contact surfaces of the equipment
need to be validated. Consideration should be given to non-contact
parts into which product may migrate. For example, seals, flanges,
mixing shaft, fans of ovens, heating elements etc.
2. Cleaning procedures for product changeover in the case of
marketed products should be fully validated.
3. Generally in case of batch-to-batch production it is not
necessary to clean after each batch. However, cleaning intervals
and methods should be determined.4. 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 program, 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.5.
Companies may consider a periodic revalidation of cleaning methods,
which are subject to variation (i.e. manual procedures etc.), as an
additional precaution.
Control of change to validated cleaning procedures is required.
Re-validation should be considered under the following
circumstances:
6. Re-validation in cases of changes to equipment, products or
processes; and
7. Periodic re-validation at defined intervals.
Q4. What critical parameters need to be looked at during
cleaning validation?A. All pertinent parameters should be checked
to ensure the process as it will ultimately be run is validated.
Therefore, if critical temperatures are needed to effect cleaning,
then these should be verified. Any chemical agents added should be
verified for type as well as quantity. Volumes of wash and rinse
fluids, and velocity measurements for cleaning fluids should be
measured as appropriate. In detail the following parameters are to
be considered during cleaning procedure and validation:-A.
Equipment parameters to be evaluated Identification of the
equipment to be cleaned Difficult to clean areas Property of
materials Ease of disassembly Fixed or not
B. Residues to be cleaned Cleaning limits Solubility's of the
residues Length of campaigns
C. Cleaning agent parameters to be evaluated Preferably
materials that are normally used in the process Detergents
available (as a general guide, minimize use of detergents
unlessabsolutely required) Solubility properties Environmental
considerations. Health and safety considerations
D. Cleaning techniques to be evaluated Manual cleaning CIP
(Clean-in place) COP (clean-out-of-place) Semi automatic Automatic
Time considerations Number of cleaning cycles
Q 5 What number of cleans should be run in order to validate a
cleaning procedure
A. At least three (3) consecutive applications of the cleaning
procedure should be performed and shown to be successful in order
to prove that the method is validated. Equipment which is similar
in design and function may be grouped and a worst case established
for validation. However, companies should evaluate each situation
individually
Q 6 What is the maximum time allowed after cleaning with water
as last rinse?AEquipment should not be left with water in it after
cleaning. The last step of the cleaning procedure involve drying
with solvent or flushing with Nitrogen, thus ensuring that there is
no opportunity for microbial growth
