Cleaning of Equipment

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.

Cleaning Agent and Surface Interactions

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.

Cleaning Agent and Surface Interactions

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.

Other Contaminants to be Removed

 

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.

Microbiological Contaminants

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

Cleaning Agents….

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

 

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.

Types of Residue

 

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.

Residues and Residue Removal

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

Cleaning Method Groupings

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.

Manufacturing Equipment Grouping

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.

Product Grouping

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.

Product Grouping

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.

Product grouping

 

A GMP HUB - ENRICH YOURSELF

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.