The cleaning of porous equipment is a concern due to the ability of the surface to absorb drug.
In this case, dedication of the equipment would be the preferred choice. If the porous equipment or part cannot be dedicated, then cleaning procedures for soaking the material in a solvent or extracting absorbed drug may be required.
In these cases the sampling practices may need to be more stringent to ensure that absorbed drug and/or residual impurities are removed during the cleaning process.
Clean-out-of-place equipment includes such items as wash tanks used to clean small parts or parts removed from large equipment.
These systems usually have some sort of automated or programmed
control system.
One example is a recirculating bath used for cleaning small parts, pump components,
gaskets and other parts removed from larger equipment.
Clean-out-of-place systems may also include dishwasher type cabinets where small manufacturing vessels, drums or hoppers can be loaded inside the cabinet and cleaned.
The placement of the parts, disassembly of equipment and loading are
critical to the success of cleaning when using clean-out-of-place systems.
The term "Clean-in-Place" generally refers to an automated system that consists of a recirculation
system which uses various tanks and a return system such as an educator or return pumps.
A system of piping delivers the cleaning solution to the equipment and returns it to a motive or recirculation tank.
There is usually a pre-rinse tank and a final rinse or purified water rinse tank.
The equipment utilizes spraying devices to provide coverage and physical impingement of the cleaning solution of the equipment surfaces.
The spray-balls may be stationary or moving (e.g., rotating, oscillating).
These systems are commonly used to clean large pieces of equipment such as manufacturing tanks,blenders, fluid bed dryers, reactors and fermentation tanks.
The CIP system need not have a recirculation system, i.e., it may be a single pass system where appropriate.
When cleaning solutions are recirculated and reused, it is important to assess their suitability for
subsequent use.
Continuous flow systems must ensure that there is no possibility of "backflow" to
previous steps in the process.
Bulk pharmaceuticals are typically manufactured within closed systems increasingly equipped with automated or semi-automated CIP equipment.
The mechanical qualification of flow rates, pressures,and spray ball patterns must be established.
2.Semi-Automated
As opposed to manual cleaning, semi-automated cleaning includes various levels of automatic
control.
At one extreme this could consist of simply manually removing gaskets/fittings for
manual cleaning prior to automated CIP of a tank or disassembly of a pump prior to cleaning
in an automated COP system.
At the other extreme, the operator may use a high pressure
spray device to clean a surface or may simply open and close water valves supplying spray
balls inside a vessel.
This level of cleaning approaches the definition of manual cleaning but
often requires more sophisticated equipment to assist the operator.
3.Automated
Automated cleaning typically does not involve personnel intervention. The system is usually
programmable for the various cleaning cycles.
These types of cleaning systems provide consistent cleaning due to the automation of the process.
Critical cleaning parameters for automated cleaning may include the volume of cleaning
agents, volume of rinse water, flow rates and temperature of wash and rinse solutions,
duration of wash and rinse cycles, pressure of solution, operating ranges and detergent
concentration.
Disassembly of equipment may still be necessary to allow for complete
cleaning or to allow for the separate cleaning of delicate parts.
In an automated cleaning system, the cleaning may be controlled through relay logic, a
computer or PLC (Programmable Logic Controller).
The control system is an integral and critical part of the overall cleaning process. The control system regulates the cleaning cycles,
addition of cleaning agents, temperature, time and other critical cleaning parameters.
There may also be a control interface or operator interface to start the process, stop the
process, monitor various stages of the process and change the process sequence. Given the
increased complexity of the newer PLC and computer interfaces, training and validation are
important issues that impact the ability of the system to provide consistent cleaning. The
validation of control systems and the change control policies which govern them are critical
to the success of the cleaning process
Three broad definitions of cleaning processes follow. The distinctions between these processes is
critical to the establishment of an appropriate cleaning validation program.
1.Manual
Manual cleaning is typically defined as the direct cleaning of equipment by a trained
equipment operator using a variety of hand tools and cleaning agents.
Although some process parameters may be monitored by gauges, the regulation and control of these parameters is the responsibility of the operator.
Critical cleaning parameters for manual cleaning may include: the volume of cleaning agents,
volume of rinse water, temperature of wash and rinse solutions, duration of wash and rinse
cycles, pressure of solutions, and detergent concentration.
It is important to specify in writing the extent of the equipment disassembly to ensure the reproducibility of the cleaning process.
In a manual cleaning validation program, the critical factor is the ability to provide a
reproducible process.
The control of manual cleaning is accomplished by operator training,
well defined cleaning procedures, visual examination of equipment after use and prior to the
next use, and well-defined change control programs.
One benefit of manual cleaning is that the operator is cognitive and able to adjust to and report changing conditions.
The cleaning processes used in our industry rely upon solubilization, chemical reaction and physical
action for residue removal.
It is possible to optimize the solubilization of the drug and still not
achieve clean equipment.
Often the physical action associated with cleaning and the disassembly of
the equipment determine the success of the cleaning process.
A number of variables should be taken into consideration when designing equipment and in the
development and performance of the cleaning process.
These variables include but are not limited to the equipment surface characteristics, equipment geometry, equipment composition, the cleaning
agent, temperature and flow rate of cleaning agents and time of exposure.
For manual procedures, other factors, such as the detailed steps of the cleaning process and operator training, play a large
role. In both manual and automated cleaning, the disassembly of equipment may be necessary for
effective, reproducible cleaning.
It is important to consider potential interactions that the cleaning agents may have with the equipment
surfaces. Glass, stainless steel, ceramic, plastics and various synthetics fibers may interact differently
with cleaning materials.
When examining equipment for types of residue, it is important to remember that the equipment itself should not contribute contaminating agents.
Lubricants, surface coatings and sealants must all be reviewed during the equipment design so that they present no danger in leaving behind residues that will adulterate products.
For sterile products, the operation of the equipment during cleaning should
not generate particulates.
In keeping with CGMPs, equipment must be non-porous, non-reactive,
non-additive and non-adsorptive.
For non-aqueous processes where water is used in cleaning, it may be necessary to validate post cleaning drying periods.
The presence of residual water after cleaning may result in microbial or
endotoxin contamination.
Certain formulations such as parenterals, ophthalmics, semi solids, oral solutions and topicals may require control of microorganisms prior to further processing.
In these instances, product contact surfaces should be evaluated for microbial contamination in conjunction with the overall cleaning validation program.
Sampling and enumeration methods used for environmental surfaces may be readily adapted for this purpose.
Microbial limits are established based on the route of administration and the nature of the product
itself (biocritical, hostile, etc.).
In addition to numeric limits, consideration should be given to
ensuring the absence of specific, objectionable organisms based on the nature of the product (S.aureus, E. coli, and Pseudomonas sp.)
For parenteral products, similar controls are necessary to limit the amount of endotoxins on product contact surfaces.
Control of microbial contamination for other dosage forms and processes may also be appropriate
Certain formulations such as parenterals, ophthalmics, semi solids, oral solutions and topicals may require control of microorganisms prior to further processing.
In these instances, product contact surfaces should be evaluated for microbial contamination in conjunction with the overall cleaning validation program.
Sampling and enumeration methods used for environmental surfaces may be readily adapted for this purpose.
Microbial limits are established based on the route of administration and the nature of the product
itself (biocritical, hostile, etc.).
In addition to numeric limits, consideration should be given to
ensuring the absence of specific, objectionable organisms based on the nature of the product (S.aureus, E. coli, and Pseudomonas sp.)
For parenteral products, similar controls are necessary to limit the amount of endotoxins on product contact surfaces.
Control of microbial contamination for other dosage forms and processes may also be appropriate
When cleaning agents are used to aid the cleaning process, it is important to remember that their
removal must be demonstrated (i.e., validated).
For this purpose, it is necessary to know the ingredients contained in the cleaning agent. The cleaning agents are multi-ingredient products and often the supplier considers the formulas proprietary or trade secrets.
In most cases, the supplier should divulge the ingredients, but may not disclose the amounts or composition of the cleaning agent formulation.
Material Safety Data Sheets (MSDSs) are essential.
Once the ingredients are known, the company must then determine the worst case ingredient in the cleaning agent.
Fortunately, most suppliers of pharmaceutical cleaning agents use only materials that are water soluble and removal of the cleaning agent is not a problem.
However, this can not be assumed and must be demonstrated by actual validation of the removal process, whereby samples are taken, analyzed and compared to pre-determined limits.
Cleaning agents, such as detergents, often aid in the physical removal of residues from surfaces.
Simple water rinses may be adequate to effect the removal of highly soluble materials, but may not
work as well with insoluble materials or those with a combination of properties.
In these cases, agents can be selected which assist in the removal of residues.
Alternating acid and base rinses is especially effective for removing certain proteins.
When establishing a cleaning program, it is important to first identify the substance to be cleaned.
Residues have physical and chemical properties which will affect the ease with which they are
removed from surfaces.
Degree of solubility, hydrophobicity, reactivity and other properties will
affect the characteristics of these residues during the cleaning process.
The type of cleaning and cleaning agents to be used must be chosen carefully according to the chemical and physical properties of the residues to be removed.
High levels of residues from manufacturing, packaging and cleaning procedures can lead to product contamination.
The purpose of validated cleaning procedures is to ensure that potential
contamination is consistently removed from the manufacturing and packaging equipment and
contamination is prevented
The use of a single cleaning agent will greatly reduce the work required to determine if residues of
the agent remain after cleaning.
For multi-product facilities, it may be necessary to use several
different agents to remove the various types of excipients that are present in different products. When considering the product formulation and equipment groupings, it is appropriate to also consider and subdivide systems based upon the cleaning agents utilized on those systems.
The agent grouping should display analogous profiles in the ability to remove similar product formulations if all other cleaning method variables are the same.
Care must be taken to ensure that worst-case products are chosen.
Typically, this approach is best if used in combination with other groupings.
Groupings should help to develop baseline data on which to establish the ongoing validation program.
New products should be added to the grouping or tested if they fall outside of the established
baseline.
As mentioned in the discussion of utensils and small equipment, it may be appropriate to group
cleaning studies based upon the utilization of a single cleaning method.
The validation of the cleaning procedure may be conducted almost independently of the equipment for which it is used.
As long as the range of equipment configuration and product formulation are used to challenge the cleaning method, this grouping, when scientifically applied, is as appropriate as any of the other grouping philosophies.
When establishing priorities of the equipment to be tested, it is important to evaluate the function of the equipment.
Major process equipment should be included in any cleaning validation program.
Major process equipment, which can be defined as having a unique identification or asset number, is often the first priority.
Minor equipment, such as utensils, small parts, and smaller equipment may
be validated separately.
In the case of minor equipment, it may be appropriate to evaluate a cleaning
procedure for miscellaneous parts and attempt to validate the range of small parts in terms of
complexity and size.
Companies may choose to selectively perform cleaning validation studies on representative groups
of equipment.
For equipment groupings, form and function define the criteria for the grouping
philosophies.
Equipment which is similar in design and function, perhaps differing only in scale, may
appropriately be grouped when performing validation testing.
Throughout the validation studies,
however, scientific principles must be followed.
The cleaning method may be validated on the largest
and smallest scale equipment within the grouping if the same cleaning procedures are to be
implemented.
A third example might be the group composed of several products having the same active ingredient and differing only in the concentration of the active ingredient.
In this case, it would be reasonable to select the product having the highest concentration of active since this product would present the greatest cleaning challenge.
As these examples illustrate, the most important aspect of the grouping is the preparation of a logical and scientific rationale justifying the grouping and the selection of the worst case representative.
In certain cases, a clear cut worst case may not emerge. In those instances, it may be appropriate to select two or more “worst cases” to represent the group.
It is unlikely that a single worst case product could apply to an entire line of products having
significantly different formulations and dosage forms.
Once the product groups have been established, the next step is to determine the so-called “worst
case” representative of each group. This may be done according to toxicity, solubility or the presence of ingredients known to be difficult to clean, such as insoluble dyes.
There is no “hard and fast” rule for this selection. In some cases, a combination of these parameters may be used. For example, if a group consisted of 5 products, four of which were cough/cold formulations and the fifth a cytotoxic product, then the cytotoxic product would be a logical choice as the worst case product.
Another example would be a group composed of 8 products of similar potency.
In this case, the worst case selection might be made on the basis of solubility. Again, the choice of the least soluble product in the group as the worst case product would be easy to defend.
A common basis for grouping is by product.
The grouping is usually based on the formulation or the
dosage form of the product. When this approach is used, the company’s products are divided into
groups according to the dosage form and then according to formulation.
For example, a company might have 10 tableted products, 6 ointment products, and 4 liquid products. In this case, the first
evaluation would be that the products fall naturally into 3 broad groups. However, if 6 of the tableted
products were manufactured by a wet granulation process, whereas 4 of the products were
manufactured by a dry, direct compression method this would be a basis for subdividing the tablet
group into 2 subgroups. Likewise, if 2 of the liquid products were suspensions and the other 2 liquid products were true solutions, this would also create 2 subgroups for this group.
Thus, the hypothetical company would actually have 5 groups of products for cleaning validation purposes.
