Cleaning
Validation: to understand cleaning validation it is important first to
understand, how cleaning is done in pharmaceutical manufacturing?
Important
aspect of cleaning in pharmaceutical manufacturing is to prevent cross
contamination of one product to another, and to prevent microbial
contamination, proper and efficient cleaning procedure is one aspect by which
the pharmaceutical company can ensure that contamination of one product to
another product does not occur.
It’s
just not sufficient to have a proper and effective cleaning procedure but the
cleaning procedure should be easy and should yield results meeting the limit or
complying with the limits to minimum carry over limit of previous product and
limit for traces of cleaning agent and rinse water and swab tests results
consistently. Almost a nondeductible level of previous product is
desirable, and the rinse water or swab test also has no detectable, very
negligible amount of the cleaning agent that is provided in the specifications.
As well as the microbial load over the surface of the equipment should meet the
requirements of good manufacturing practices guidelines.
Cleaning
procedure:
Initial
cleaning of equipment is done with raw water and scrubbing the surfaces of the
equipment. Followed by soap solution and scrubbing, Suitable solution of soap
or surfactant with suitable concentration is added on the surfaces of the
equipment and again scrubbing is done.
In
case of CIP systems, the soap solution is added in a soap solution tank, from
which it is sprayed through a spray ball into the manufacturing equipment
covering every point inside the equipment.
How
to decide the concentration of soap solution for cleaning in pharma
manufacturing?
Molecule
deactivating agents:
In
case of steroid drugs and potent drugs manufactured in equipment, the
manufacturing vessels are added with a strong oxidizing agent and solution of
dilute sodium hydroxide or dilute solution of acid, to break down the molecule
so that the byproduct if any is easily removable and easily cleaned away with
soap solution.
Soap
solutions or pharmaceutical cleaning agents are formulated which includes such
deactivating agents, which easily allow the traces of such potent or peculiar
smells like methyl salicylate or any fragrances added in topical preparations
can be deactivated and removed easily during washing with water.
How
to decide the concentration of cleaning agent solution for cleaning in
pharmaceutical manufacturing?
Concentration
of cleaning agents should be initially decided upon by using it by making
different concentrations on empty or equipment which are not used or yet to be
used, by adapting the same procedure as that of regular procedure in the SOP.
The
best fit lowest and optimal concentration should be considered after
observation of the results obtained from cleaning of equipment with different
concentrations. And different cleaning agents.
One
cleaning agent will be effective for cleaning after a particular product and
that may not be effective for cleaning of other product, evaluation of same
should be done in small scale and identify a broad spectrum effective cleaning
agent and product specific, hard to clean product cleaning agent in small scale
pilot plant, while cleaning validation should confirm the efficacy of these
cleaning agents.
Contact
period of soap solution and equipment surface is important in achieving
cleaning, therefore even if CIP systems circulation of soap solution in
manufacturing vessels, equipment’s, is done for a defined period, about 15 to
30 minutes, and after which soap solution is drained off and removed by
circulation of hot water. Transfer pipes, accessories, transfer systems ducts, pipes,
storage bins, pressurized vessels, etc. are circulated with cleaning agent
solution for appropriate time.
In
CIP you need to provide input for the circulation time for soap and rinsing
water and final rinsing.
Number
of washing with hot water to remove soap solution and debris of previous
product:
Higher
or more the number of washing better is the solubility of material, hence
giving the number of washing to equipment with hot water after application of
soap should be identified so that the removal of all traces of soap is
facilitated completely. Final rinsing with purified water:
Final
rinsing of equipment with purified water is done
to remove the traces of raw water, hot purified water is circulated through CIP
and from piping and ducts through which the product transfer and handling is
done.
Cleaning
validation What is cleaning validation?
Cleaning
validation is validation of cleaning procedures adapted for the equipment, in
manufacturing, filling etc. Validation is the process of gathering data as documentary
evidence and reviewing and verifying through documentary evidence that the
adapted procedure, process CIP is capable of producing predetermined, desired
consistent results of cleaning, and reducing the microbial contamination from
surface of the equipment to the acceptable level.
For
cleaning validation, a pharmaceutical manufacturing company has to decide on
which product should be considered first for validation of cleaning procedure
for equipment after manufacturing of that product.
There
are two most important criteria for selection of product for doing cleaning
validation.
1. LD 50
value
2. Worst
to clean product.
Above
two criteria when considered during selection of the product it will fulfill
the objective of the process of cleaning validation.
Consideration
of LD 50 value for consideration of product for doing validation of its
cleaning:
LD 50
value is a value that indicates dose of a drug that is lethal to 50 % of the
population of animals in the study. It is determined during initial safety
study while doing acute toxicity study of a drug molecule.
Lower
is the LD 50 value of its highly toxic molecule, therefore during considering
any product for doing cleaning validation first matrix of all products and the
LD 50 values of the API used in the product, since the excipients mostly are
inert and do not have any toxic effects. In this table the product with API with
lower LD 50 value is arranged on top and goes down in the table in increasing
order.
Worst
to clean product, Hard to clean product:
A
product with higher level of water insoluble API or excipients, odoriferous
product imparting staining like coloration example of colored API ivermectin,
Beta carotene etc.
These
products should be included in the validation master plan for doing cleaning
validation.
A
matrix of hard to clean products and products with API with lower solubility in
water should be prepared.
A
comprehensive matrix presenting a LD 50 matrix and matrix of hard to clean
product and product with API with lower solubility in water should be prepared.
Hard
to clean and products with API insoluble or lower solubility in water should be
placed on along with lower LD 50 products.
In
event there are two products coming on top one with lowest LD 50 value and
product with insoluble API then both products can be considered in cleaning
validation depending on the nature of product.
Minimum
carry over limit for residue after cleaning.
Regulatory
aspects: US FDA guidelines on cleaning validation are provided in
21 CFR PART 211.67 mentioned that periodic cleaning and sterilization of
equipment must be done so as to prevent cross contamination, to prevent threat
of contaminants going into drug products and alter its safety and efficacy.
Standard
operating procedure should be available with training on how to conduct
cleaning validation, a protocol for doing cleaning validation is required to be
prepared and approved by Quality assurance.
Sampling
plan sampling procedure sample points and method of estimation of residues,
collected data and its tabulation and method of evaluation should be provided
in protocol for cleaning validation and in the report of cleaning validation.
Responsibilities
of each unit or persons functioning should be clearly defined.
Cleaning
methods:
Clean
in place: as it is known as CIP automated systems and used in this method.
Clean
out of place: where the equipment parts are disassembled and taken into the
washing area and cleaned.
Sampling
for testing for cleanness:
Direct
samples taken with swab from the surfaces, sometimes the swab cannot be taken
from the inner part of equipment therefore indirect samples like water rinsed
over those parts are taken and tested for residue.
Quality
assurance should first Annalise the worst to clean spots and corners and a
sampling for swab and rinse water sampling plan and location is decided.
Evaluation
of cleaning:
Physical
observation: Physical observation with naked eyes and with magnifying
glasses can be done, facility for light, or torch used to observe the inner
side of the surface. Quality assurance person should do this physical
observation after cleaning along with the doer department.
Estimation
of residues left over: HPLC method used for estimation of
the API and drug product under the cleaning validation activity is used, traces
of soap can be estimated with HPLC or spectrophotometric. IR can be used
for identification of soap residue if required.
Limit
residues left over: Not more than 0.1% of the normal
therapeutic dose of a product should appear in the maximum daily dose of
another product.
Microbial
load test: Swab test, contact plate techniques
can be used for microbial evaluation of cleaned equipment. The area also is
cleaned therefore the microbial load test for the respective area should also
be done.
Limit for Microbial load over cleaned equipment: no more than 20 CFU (colony-forming units) for bacterial counts, no more than 2 CFU for molds, and/or no more than 25 CFU/25cm2 of contaminants in a sample
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