Special Report: Points to consider
01/01/2000
Good manufacturing practice recognizes that cleaning is critical to the quality of pharmaceutical products.
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By Russell E. Madsen
In recent years, cleaning has grown in importance in the pharmaceutical industry.
The first step in establishing a cleaning validation program is to characterize the types of cleaning used in the facility. Photos courtesy of Cintas Cleanroom Resources.
The current good manufacturing practices (cGMP) regulations in the United States, Europe and other parts of the world have provided the pharmaceutical industry with general guidance for cleaning requirements. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." " Section 211.182 of part 21 of the CFR indicates that cleaning procedures must be documented appropriately and that a cleaning and use log should be established. In addition to cGMPs, various inspectional guideline documents published by the FDA contain expectations regarding cleaning.
 Photo courtesy of Texwipe. |
It has always been the responsibility of the regulated industry and the regulatory agencies to interpret the cGMPs and to create programs and policies that establish the general requirements as specific practices. Recognizing the importance of the relationship between cleaning and product quality, regulatory agencies are demanding greater evidence of cleaning effectiveness through validation or verification.
The cleaning continuum
 Photo courtesy of Cintas Cleanroom Resources. |
Progress to a consensus in approach in the industry has been slowed by the number and complexity of issues surrounding the cleaning process and the variety of facilities, products and equipment in use. The limits of the cleaning continuum represent the extremes in the range of operating differences found within the industry which preclude a uniform approach. At each end of the continuum, the cleaning validation requisites are either simple or complex. Recognition that there are many of these coupled limits, and that each cleaning process has a unique place within each level of the continuum, explains why specific industry-wide approaches have been so difficult to develop.
The cleaning continuum provides points to consider in any cleaning validation program. The continuum helps firms to establish the parameters critical for individual products, thereby enabling them to set priorities, develop grouping philosophies and establish the scientific rationale to govern the cleaning program. The continuum will assist in determining which processes, equipment and products represent the greatest concerns and may help to establish the criticality of cleaning limits and methods. The continuum should be used during the initial phases of defining a cleaning validation program or during new product development.
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The cleaning continuum includes: cleaning program criteria, equipment characteristics, quality attributes of equipment design, formulation/product attributes, analytical methodology and manufacturing/pro-cess attributes. All of the factors in the continuum directly affect the ability to clean; however, their relative importance and criticality may be different from one company to another.
Cleaning program
When establishing a cleaning validation program, it is important to first characterize the types of cleaning used in the facility. The cleaning methods can reveal important factors with regard to process control, process reproducibility, the best ways in which to challenge the process, the best ways in which to collect samples and the best ways in which to monitor cleaning effectiveness during routine cleaning.
Automated Cleaning —Manual Cleaning: Automated cleaning will usually provide reproducible results. Process control is inherent in automated systems and process monitoring is frequently integral with the control system. Automated systems may not adjust to present conditions. The validation of an automated system requires that the cycle is proven to be rugged and will provide reproducible results under a given range of operating conditions. Control system validation is a large part of the validation of an automated cleaning system.
Manual cleaning is a universal practice within the pharmaceutical industry. There are many pieces of equipment for which construction or configuration make manual cleaning a necessity. 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. It may be desirable to identify worst case cleaning situations (in terms of operator experience or cleaning methodology) for validation purposes. With manual cleaning, concern must also be given to the ruggedness of the method. Successful reproducibility is a function of strict adherence to written procedures.
Clean-In-Place (CIP)—Clean-Out-of-Place (COP): the cleaning of large pieces of equipment may be performed in the equipment's permanent location, generally in a configuration similar to that in which it is used. This procedure is widely known as clean-in-place (CIP). Smaller equipment items are frequently transported to a designated cleaning or wash area where the cleaning procedure is performed. This practice is known as clean-out-of-place (COP), but the term is not as prevalent as its counterpart.
The additional activities involved with transport of equipment to and from the wash room, component identification, the elimination of cross-contamination potential during transfer, and cleaning and storage prior to use make the validation of COP procedures somewhat more difficult than the comparable CIP activity. The need for manual manipulation is an integral part of many COP procedures and requires detailed procedures and training. The manual manipulation makes COP concerns similar to those of manual cleaning in place.
The use of automated washing machines to COP smaller items is an important part of many systems. The use of these systems reduces the differences between CIP and COP significantly. These systems are considered highly reproducible in their cleaning performance and are gaining wide acceptance.
Equipment characteristics
Equipment usage during production is another aspect to consider in establishing a cleaning validation program. It is important to understand not only the range of products that are likely to come into contact with the various equipment surfaces, but also the role that the equipment plays in the production train. This will help to establish the contamination and cross-contamination potentials of the equipment.
Equipment design characteristics, as established during product development, are often driven by equipment functionality and the requirements of the process. With the current emphasis on cleaning validation, it makes sense that cleanability be a key criterion in the design of equipment.
Dedicated—Non-Dedicated Manufacturing Equipment: Dedicated equipment is used solely for the production of a single product or product line. Concerns over cross-contamination with other products are markedly reduced. Dedicated equipment must be clearly identified with the restrictions of use to prevent errors during cleaning and preparation.
Where the same piece of equipment is used for a range of product formulations, (i.e., nondedicated equipment), the prevention of cross-contamination between products becomes the main objective in the cleaning validation effort.
Dedicated—Non-Dedicated Cleaning Equipment: The issues of dedicated and non-dedicated equipment can also arise when considering the equipment used for cleaning. CIP systems, for example, are frequently used for many different tanks in a single facility. Inherently, the design of CIP systems should preclude cross-contamination through appropriate valving and back-flow prevention. Care should be taken with shared devices which apply cleaning agents, such as spray balls or spray nozzles which, themselves, may require cleaning. Certainly any recirculation within the CIP system should be configured carefully during system design and monitored closely during routine operation.
COP equipment, such as an ultrasonic sink, may also be used for multiple equipment loads. With cleaning apparatus such as the sink, the removal of potential contaminants from the sink itself is a concern. Sinks and washers frequently use recirculation systems to economically remove residuals from surfaces without undue waste. The cleanliness of the recirculated materials should be evaluated during cleaning validation to ensure that contaminants are not being redeposited on the equipment to be cleaned.
Non-Product Contact—Product Contact Surfaces: Traditionally, the validation of cleaning has focused on product contact surfaces. Programs for the elimination of cross-contamination must address non-product contact surfaces if they are to be truly effective. In practice, cleaning validation requirements may change with non-product contact surfaces in accordance with the less critical nature of these areas. When establishing the requirements for non-product contact surfaces, it is important to review the possible interactions of that area with the process.
Non-Critical Site—Critical Site: Critical sites are those locations in which a contaminant is in danger of affecting a single dose with a high level of contamination. Critical sites often require special cleaning emphasis. It may be appropriate to establish more intensive sampling schedules for critical sites, set tighter acceptance criteria for critical sites and ensure that enough detail is included in cleaning procedures to provide for reproducible cleaning of critical sites.
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The cleaning of equipment is closely tied to the type of materials being removed from the surface. Photo courtesy of Terra Universal.
Minor Equipment—Major Equipment: The distinction between "major and "minor" equipment is not a definitive one. The cGMPs make mention (211.105) of major equipment but are silent on the subject of minor equipment except with regard to items described as utensils (211.67). Despite this failure with the cGMPs, it is necessary to identify those pieces of equipment (major) central to the production process and those pieces of equipment (minor) that perform a secondary role.
 Photo courtesy of Terra Universal |
Typically the cleaning of major equipment will be the subject of the individual, highly specific standard operating procedures (SOPs). In contrast, minor equipment and utensils are often cleaned using broadly defined procedures which describe the methods to be used in general terms.
 Photo courtesy of Terra Universal |
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Materials of construction
The materials of construction of the equipment should be considered when establishing a cleaning validation program. The attributes of the surface to be cleaned will define the residue to surface interactions, identify possible contaminants and point to areas that may not be readily cleaned or accurately sampled.
Equipment should not be reactive, additive or adsorptive with the process materials that contact them. The use of porous surfaces for multiple products should be avoided (filters, filter bags, fluid bed drier bags, membrane filters, ultra filters). Any surfaces that have these properties will require review during cleaning validation evaluations to ensure adequate product removal and minimize the potential for cross-contamination. The interaction of cleaning agents with surfaces that are likely to display these properties (e.g., seals, gaskets, valves) should be assessed.
Product attributes
The cleaning of equipment is closely tied to the type of materials being removed from the surface. The product formulation is often the key in establishing appropriate cleaning acceptance criteria, challenge methods and sampling techniques.Low Risk—High Risk Drugs: The residual limits used for cleaning validation are often closely related to the allergenicity/toxicity/potency of the materials in question. The limits are eased when the materials being removed are generally of lower pharmacological activity. At the other extreme, there are numerous materials and formulations where even minute quantities can have pharmacological activity. The equipment and the procedures used to clean the equipment might be identical, yet the production of materials with known adverse effects may require that tighter limits be achieved. Cleaning, sampling and analytical methods may need to be refined to a high degree of sensitivity to ensure that the equipment has been properly cleaned.
Many companies have used dedicated facilities or equipment or have conducted cleaning verification to circumvent some of the inherent difficulties in processing high risk drugs. The difficulties of reproducibly demonstrating successful cleaning may make it operationally easier to dedicate the equipment or facility to the production of a single product rather than attempt to clean to the necessary level.
The route of administration of a product may affect the level at which the product is found to be allergenic, toxic or potent. Generally speaking, injectable products, intra-ocular formulations, and some inhalants that provide direct access to the systemic circulation systems of patients are in much greater concern in terms of cross-contamination.
Highly Characterized—Poorly Characterized: The introduction of pre-approval inspection requirements for NDA and ANDA approval has resulted in greater scrutiny on documentation describing the development of the formulation. Regulatory agency expectations for cleaning validation are formidable within the confines of marketed product manufacturing (typically highly characterized products) but placing the same requirements upon developmental drugs (typically poorly characterized) makes cleaning validation even more difficult. During product development, the formulation, process and equipment to be used in production are evaluated to ensure a consistent process for commercial scale manufacture. Before the final equipment selections are made, however, a variety of equipment combinations may be tried, resulting in a vast array of cleaning combinations.
In addition to the myriad cleaning processes that must be evaluated, there are additional difficulties: appropriate limits for active agents must be selected; this limit might be based upon a not-yet-identified therapeutic dose. Alternatively, using the lowest dose, or considering using the worst case might save time on scale up, provided the appropriate assays for these levels have been developed and validated. Other difficulties include the requirement that appropriate analytical methods must be developed for all formulations. Clearly, while the validation of cleaning is a difficult task in a production facility, the unknowns inherent in clinical product manufacturing, where the products is poorly characterized, make the task even more challenging.
Other areas where products may be poorly characterized include bioprocesses and syntheses where vast numbers of related molecules may be formed, in addition to the primary product. While there are generally requirements that all of these potential contaminants developed during the manufacturing process be identified, these materials may not be characterized well enough to have specific, low-level assays developed. The establishment of appropriate limits is equally complicated and may not be feasible.
Non-Sterile—Sterile: The production of sterile formulations increases the extent of cleaning operations relative to non-sterile products. Sterile manufacturing facilities must control microbial, endotoxin and particle levels to a degree not common with non-sterile products. Not only are the number of concerns increased but the nature of these contaminants makes their successful removal (and their validations) more difficult. Sampling methods for these contaminants are more subjective, the analytical methods more demanding, and the validation generally more difficult.
Concerns relative to microbial and particulate control are lessened in the production of nonsterile products but are still important. Practices that minimize the potential for contamination by objectionable organisms are common in the manufacture of non-sterile formulations such as oral liquids and topical products.
Formulation attributes
Attributes of the formulation have a great influence on the ability to clean. In general, solid and liquid formulations represent the range of physical product attributes and soluble and insoluble represent the ability of products within the continuum to react with the cleaning agents.
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Use of dedicated facilities or cleaning verification can help circumvent some of the inherent difficulties in processing high risk drugs. Photos courtesy of Terra Universal.
Solids—Liquids: The differences in the cleaning of equipment used for solid and liquid formulations are quite significant. The distinction between these formulation types is related to how contamination might be left on the equipment and dispersed in subsequent products. Liquid formulations may have greater ability to penetrate equipment seals and joints, hindering their removal. In contrast, solid formulations may have unique abilities to form aggregations of product. This clumping may inhibit wetting by cleaning agents, thereby limiting the ability to rinse the residual product away.
 Photo courtesy of Terra Universal |
The distribution of the contaminant is often considered quite different for solid and liquid formulations as well. Liquid products are often considered to have superior dispersion of active ingredients uniformly across surfaces, while solid products are expected to have more point-to-point variability, based primarily on equipment configuration.
Soluble (Active or Excipient)—Insoluble (Active or Excipient): Soluble products are often easily removed during cleaning by solubilizing the product, both active and excipient, so it can be rinsed away. Insoluble materials, on the other hand, will resist going into solution and must be removed by a more physical means or by the addition of cleaning agents that result in increased wetting, emulsification or solvation of the materials.
Some products may demonstrate both soluble and insoluble behaviors with the raw materials of the final product.
Operational issues
Such operational issues as the number of products manufactured, the use of campaigns and utilization of equipment, and the complexity of the equipment impact the design of the cleaning validation program.
Single Product Facility—Multiple Product Facility: The circumstances surrounding a single product facility are analogous to those for dedicated and non-dedicated equipment. In those instances where a facility, which might be a separate building on a large site, produces only one product, the validation requirements are simplified by the elimination of cross-contamination concerns.
Multiple product facilities (also referred to as multi-product or multi-use facilities) clearly represent a more difficult challenge. Procedurally, steps must be taken in a multiple product facility to ensure that cross-contamination potential is eliminated. Change-over of equipment from one product to another must be carefully controlled. After cleaning validation is completed, monitoring programs may be warranted to ensure that all controls are in place and that limits established during cleaning validation are maintained.
Campaign Production—Batch Production: Within a multiple product facility, a production campaign may be used to minimize cross-contamination between lots. For campaign production, multiple lots of a product or product family are produced in the same equipment. In some instances, it is deemed appropriate to interrupt this production run with what is sometimes considered a less stringent cleaning procedure and evaluation between lots. Once the campaign has been completed, the company will perform an intensive cleaning of the facility and equipment before beginning the production of a different product.
In long campaigns, the potential for contamination or product residue build-up with time can result in concentrations higher than typical for a single lot. The repetitive production of a single product might also result in the penetration of materials into a location where single lot production might not present a problem.
Simple Equipment Train—Complex Equipment Train: An equipment train is generally recognized as a grouping of equipment or systems that function as a unit during the production of a product. The complexity of the equipment train is based on the number of discrete pieces along the train, the number of transfer or process steps and the ability to sample the equipment train as discrete items (e.g., closed systems). The complexity of the cleaning validation is directly proportional to the complexity of the equipment train.
Cleaning validation programs
Frequently, the basis of cleaning validation programs is the establishment of a plan that describes the overall validation approach. The rationale for any grouping philosophies used and the validation program to be implemented should be identified.
After the determination has been made of which product(s) and piece(s) of equipment are to be used in the validation study, the validation trials may commence. If the product is to be coated on equipment surfaces to form a trial for cleaning validation, care must be taken that the product coverage used for validation is appropriate to simulate the level of contamination that would be present in an actual manufacturing situation.
Care should also be taken in the simulation of production methods. For example, a piece of equipment that is used early in the morning may sit, contaminated with product, until the second shift starts. Having the product "dry" on the equipment, therefore, may be the worst case. It is important to consider the effect that weekends, holidays and delays might have on the cleaning schedule. It is advisable to determine the stability of material remaining on equipment for longer time periods than in a normal manufacturing sequence. Material typically may degrade, dehydrate or adhere to equipment over time. It may be advisable to establish the stability of the product in the manufacturing equipment for the longest (i.e., worst case) holding period. Regulatory inspectors are known to be interested in how the company has taken the stability and cleanability of materials into account when materials sit in equipment for long periods. The product reserved in the open container should be evaluated for product degradation studies. The validation group, user group, quality assurance group, and others are all responsible for ensuring that the test program is an accurate reflection of production.
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Equipment should be cleaned using standard operating procedures. Photo courtesy of Texwipe.
The cleaning of the equipment should proceed in accordance with the documented standard operating procedure. After the cleaning has been completed, an intensive sampling of the system may begin.
The number of trials to be performed for each system is another issue that is often debated. Most cleaning validation programs demonstrate the reproducibility of a process by three consecutive trials for a single product on a single piece of equipment. If a company chooses to pursue the grouping philosophies for the initiation of the cleaning program, it may be part of the plan to pursue the representative products and equipment with three trials each. After completion of the trials representative of the most challenging cleaning, it may be appropriate to reduce the number of trials for subsequent products that fit within the grouping baseline. If reducing the number of trials to be performed, care should be taken to identify the rationale for the product grouping and to demonstrate the equivalency of new findings to the initial results.
Many companies seek a common denominator whereby similar products may be grouped. Through this process, the company attempts to convert a complex situation into a manageable project. Typically, products are first grouped according to formulation and dosage form, including considerations of potency, toxicity and solubility. These product groupings are further subdivided by types of equipment used in their manufacture. Further distinctions are made according to cleaning method and agent.
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 formulation. For example, a company might have ten tableted products, six ointment products, and four liquid products. In this case, the first evaluation would be that the products fall naturally into three broad groups. However, if six of the tableted products were manufactured by a wet granulation process, whereas four were manufactured by a dry direct compression method, this would be a basis for subdividing the tablet group into two subgroups. Likewise, if two of the liquid products were true solutions, this would also create two subgroups for this group. Thus, the hypothetical company would actually have five groups of products for cleaning validation purposes.
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 five products, four of which are cough/cold formulations and the fifth a cytotoxic product, then the cytotoxic product would be the logical choice as the worst case product.
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 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.
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. 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.
Cleaning method groupings
It may be appropriate to group cleaning studies based on the use 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.
Cleaning agent groupings
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 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 on the cleaning agents used. 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 the established baseline.
Russell E. Madsen is vice president of scientific and technical affairs at PDA, the international association for pharmaceutical science and technology, and chairman of the pharmaceutical cleaning validation task force. This report was excerpted from PDA Technical Report No. 29, Points to Consider for Cleaning Validation.
Developing a validation protocol
by Jan Eudy, Cintas Cleanroom Resources
There are different types of validation. The most frequently used is called prospective validation. It is a validation that is planned and initiated at the beginning of the implementation of any instrumentation, process or system. It is the easiest type of validation to perform because it offers control of the validation process from the beginning. It is not started in the middle or implemented at the end of system installation.
The first step in a prospective validation is to determine its scope. This includes evaluating the vendors and their capabilities to meet requirements within the cleanroom, including the HVAC systems, electrical systems, water systems, etc. The manufacturer of each of these components is responsible for providing the documentation regarding a particular system and its suitability for use in the cleanroom. The manufacturer is also responsible for quality testing and should provide installation instructions, operating parameters, and technical support. This should be specified as part of the parameters in the purchase agreement. The documentation package is the verification of conformance that is requested from the manufacturer.
After documentation is received from vendors of equipment and for systems installed by contractors, then facility personnel develop specific standard operating procedures for those systems. For example, these procedures could include testing for non-viable and viable particles to ensure particle cleanliness and filtration efficiency inside the cleanroom. The manufacturer should provide adequate training for personnel to operate the system, including preventive and corrective maintenance. Facility management is responsible for selecting the appropriate personnel and for assigning responsibilities to each member of this validation team. These members probably have been designated in the writing of the validation protocol and are given appropriate responsibilities and authority. When the written validation protocol and test procedures are approved, then the actual testing is performed. It is performed as stipulated in the protocols, with each step being documented. Initially, there will be second-party verification of the test results to assure that the test results are correct and within specifications, and that the test results are what was expected during this validation process.
Test procedures
The tests must show not only the responses under ideal conditions, but simulated worst case scenario operating conditions should also be defined and then addressed to have in place a disaster prevention
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ecover plan. Should there be a total system failure, this plan defines the procedures to bring the system back on-line and to ensure the system operates within the required specifications.
Once these test procedures are written and the specifications defined, there should be alert and action parameters established at the limits of the system's capabilities. This will prevent the process from deviating from normal operating ranges. The system should be set to alert the process operator when the process trends toward upper or lower limits.
Jan Eudy is the quality assurance manager for Cintas Cleanroom Resources in Newburgh, NY.