Equipment
The basic good manufacturing practices (GMP) requirement is to ensure that production equipment is designed, located, and maintained to serve its intended purpose. This requirement helps ensure that active pharmaceutical ingredients (APIs) and drugs of consistent quality are fabricated. Equipment GMP are designed to prevent the contamination of drugs by other drugs, by dust, and by foreign materials such as rust, lubricant, and particles coming from the equipment. Contamination problems can occur from poor maintenance, the misuse of equipment, exceeding the capacity of the equipment, and the use of worn-out equipment.
Major equipment should be identified with a distinctive number, name, or code that is recorded in batch records. This identification requirement is intended to help document which pieces of equipment were used to make which batches of drug product.
A label indicating the status of maintenance is not required by regulations; however, records demonstrating maintenance should be available. A firm should be able to provide records documenting when a specific piece of equipment was last calibrated/maintained, the results or action, and when its next maintenance is scheduled. The absence of such documentation or failure to provide these records is considered a GMP deviation.
DESIGN
Equipment should be of appropriate design and adequate size, and the design and construction of equipment should permit cleaning, sanitizing, and inspection of the equipment. Equipment should be designed for closed or contained processes wherever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination. Equipment should be equipped with fittings that can be dismantled and cleaned, allowing validated clean-in- place (CIP) equipment to be dismantled for periodic verification. Equipment should be sterilizable/sanitizable, where appropriate, and have filter assemblies designed for easy dismantling. Equipment documentation should include design validation, installation, operation, and performance qualification documentation.
Equipment should be suitably located for its intended use. Major equipment (for example, reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified. Fixed pipework should be clearly labeled to indicate the contents and, where applicable, the direction of flow. Equipment should be part of an appropriate, defined maintenance program. Equipment should only be used within its qualified operating range, and dedicated production equipment should be provided where appropriate. Where applicable, chain drives and transmission gears should be enclosed or properly covered. Tanks, hoppers, and other similar fabricating equipment should be equipped with covers.
MATERIALS OF CONSTRUCTION
GMP requirements stipulate that equipment parts that come in contact with raw materials, intermediates, APIs, in-process drugs, or drugs should be designed and constructed so that they are accessible for cleaning or are removable. Equipment parts should be designed and constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or established specifications. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to such an extent that it will affect the quality of the product and present any hazard. Surfaces that come in contact with raw materials, in-process drugs, or drugs should be smooth and made of material that is nontoxic, corrosion resistant, nonreactive to the drug being fabricated or packaged, and capable of withstanding repeated cleaning or sanitizing. Equipment made of material that is prone to shed particles or to harbor microorganisms should not contact or contaminate raw materials, in-process drugs, or drugs.
LUBRICANTS
The design of equipment should be such that the possibility of a lubricant or other maintenance material contaminating the drug is minimized. Any substances associated with the operation of equipment, such as lubricants, heating fluids, or coolants, should not contact intermediates or APIs so as to alter their quality beyond the official or established specifications. Any deviations should be evaluated to ensure that the fitness for purpose of the material is not affected detrimentally. Wherever possible, food-grade lubricants and oils should be used.
Equipment Layout
Equipment should be arranged in an orderly manner that permits cleaning of adjacent areas and does not interfere with other processing operations. Equipment should be:
• Located to suit its intended purpose
• Located so that production operations undertaken in a common area are compatible, and so that cross-contamination between such operations is prevented
• Located to optimize the flow of material and to minimize the circulation of personnel (unidirectional flow)
• Installed to prevent any risk of error or of contamination, and to ensure that equipment is not operated where contaminants may fall into the material
• Easily cleaned, sanitized, and inspected
• Located at a sufficient distance from other equipment and walls to permit cleaning of the equipment and adjacent area
• Sealed at the base of immovable equipment along points of contact with the floor
EQUIPMENT CLEANING VALIDATION
Regulations require that APIs and drug products be fabricated and packaged in areas that are free from environmental contamination and free from contamination by another drug. Washing and cleaning equipment should be chosen and used in a manner so as not to be a source of contamination.
The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure for removal of product residues, degradation products, preservatives, excipients, and/or cleaning agents, as well as the control of potential microbial contaminants. In addition, the company needs to ensure that there is no risk associated with cross-contamination of active ingredients.
Equipment should be cleaned at appropriate intervals to prevent buildup and carry- over of contaminants (for example, degradants or objectionable levels of microorganisms). A written cleaning (sanitization) process validation program provides some assurance that levels of cleanliness in the plant are maintained and that the provisions of Sections 8 and 11 of the Food and Drug regulations are satisfied. The cleaning validation program should demonstrate that cleaning procedures are robust and effective, establish the maximum time that may elapse between the completion of processing and equipment cleaning (dirty hold time), establish the maximum time that equipment may be held clean before use (clean hold time), and document and justify the amount of carry-over from batch to batch.
Cleaning validation is used for equipment used in continuous or campaign production of successive batches of the same intermediate or API, and non-dedicated equipment cleaned between production of different materials to prevent cross-contamination.
GMP of Cleaning Validation and Analytical Methods
GMP state that a cleaning program must be implemented and be effective in preventing unsanitary conditions. Cleaning procedures for manufacturing equipment are validated based on the cleaning validation guidelines. Residues from the cleaning process itself (for example, detergents, solvents) are removed from equipment during cleaning.
It is necessary to provide evidence demonstrating that routine cleaning and storage does not allow microbial proliferation, and that analytical methods used to detect residues or contaminants are validated. The analytical methods used to detect residuals or contaminants should be specific for the substance or the class of substances to be assayed (for example, product residue, detergent residue, and/or endotoxin) and be validated before the cleaning validation study is done.
In the case of biologic drugs, the use of product-specific assay(s) such as immunoassay(s) to monitor the presence of biological carry-over may not be adequate; a negative test may be the result of denaturation of protein epitope(s). Product-specific assay(s) can be used in addition to total organic carbon (TOC) for the detection of protein residue.
The analytical method and the percentage recovery of contaminants should be challenged in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface, and to show the level of recovery and the consistency of recovery. This step is necessary before any conclusions can be made based on the sample results. A negative test may be the result of poor sampling technique. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified, and equipment should be visually examined to verify cleaning.
Cleaning Validation and Sampling, Rinsing, Rinse Samples, and Detergents
Two types of sampling that are generally considered to be acceptable are direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling:
• Direct surface sampling. Areas hardest to clean and that are reasonably accessible can be evaluated by the direct surface sampling method. This method allows establishment of a level of contamination or residue per given surface area. This method ensures that dried out or insoluble residues can be sampled.
• Rinse samples. Rinse samples allow sampling of a large surface area and of inaccessible systems or ones that can not be routinely disassembled. Limitations include insoluble contaminants or contaminants remaining on the equipment surface.
Indirect testing, such as conductivity and TOC testing, may be of some value for routine monitoring once a cleaning process has been validated. This process could be applicable to reactors or centrifuges and piping between such large equipment that can be sampled only using rinse solution samples.
When detergents are used in the cleaning process, their composition should be known to the user, and their removal should be demonstrated. The manufacturer should ensure that they are notified by the detergent supplier of any changes in the formulation of the detergent. Acceptable limits should be defined for detergent residues after cleaning. The possibility of detergent breakdown should be considered when validating cleaning procedures. Indirect testing such as conductivity and TOC testing may be of some value for assessing the effectiveness of removing the cleaning agent.
Water for injection (WFI) should be used as the last rinse for product-contact equipment to be used in the fabrication of sterile products. Purified water is considered acceptable as the last rinse for product-contact equipment used in the fabrication of non- sterile products or sterile products for ophthalmic use. Tap water should not be used in the last rinse of any cleaning procedure for product-contact equipment because of the presence of varying levels of organic and inorganic residues, as well as chlorine.
Establishment of Cleaning Validation Limits
No established standard acceptance limits exist for cleaning validation. Companies must establish limits that reflect the capability of the cleaning processes and analytical test methods used. Considerations for cleaning include evaluation of the therapeutic dose carryover, toxicity of the potential contaminant, concentration of the contaminant in rinse and swab samples, removal of cleaning agents, limit of detection of the analytical test method, and identification of critical areas (hardest to clean).
The approach for setting acceptance limits can be product-specific cleaning validation for all products; grouping into product families and choosing a worst-case product; grouping by properties (for example, solubility, potency, toxicity or formulation ingredients known to be difficult to clean); setting limits on not allowing more than a certain fraction of carryover; and different safety factors for different dosage forms.
Carryover of product residues should meet defined criteria, for example, the most stringent of criteria:
• No more than (NMT) 0.1% of the normal therapeutic dose of any product is to appear in the maximum daily dose of the following product.
• NMT 10 ppm of any product is to appear in another product.
• No quantity of residue may be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.
• For certain highly sensitizing or highly potent ingredients (such as penicillins, cephalosporins, or potent steroids and cytotoxics), the limits should be below the limit of detection by the best available analytical methods. In practice, it may mean that dedicated plants are used for these products.
If levels of contamination or residuals are not detected, it does not mean that no residual contaminant is present after cleaning. It only means that the levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample.
Documentation
Required documentation for cleaning validation includes detailed cleaning procedure(s) documented in standard operating procedures (SOPs), and a cleaning validation protocol defining how the cleaning process will be validated. The protocol should include the objective of the validation process; responsibilities for performing and approving the validation study; description of the equipment to be used; the interval between the end of production and the beginning of the cleaning procedure; the number of lots of the same product that could be manufactured during a campaign before a full cleaning is done; detailed cleaning procedures to be used for each product, each manufacturing system, or each piece of equipment; the number of cleaning cycles to be performed consecutively; and any routine monitoring requirement. Other information in the cleaning protocol includes sampling procedures, including the rationale for why a certain sampling method is used; clearly defined sampling locations; data on recovery studies, where appropriate; validated analytical methods, including the limit of detection and the limit of quantitation of those methods; the acceptance criteria, including the rationale for setting the specific limits; other products, processes, and equipment for which the planned validation is valid according to a bracketing concept; change control and revalidation; and approval by management
Manual cleaning procedures are inherently variable. Operators should be trained, monitored, qualified, and periodically assessed on the effectiveness of performing cleaning operations. Manual cleaning methods should be reassessed at more frequent intervals than CIP systems. Cleaning processes should be reassessed at defined intervals, and revalidated as necessary. As a general rule, if cleaning validation has not been performed, equipment should be dedicated to prevent cross-contamination.
Equipment Cleaning
Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carryover of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.
Cleaning GMP require that procedures contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. Cleaning procedures must strictly follow carefully established and validated methods. These procedures should include:
• Personnel responsible for carrying out cleaning procedures
• Requirement to identify equipment with contents and cleanliness status
• Intervals for cleaning/sanitizing, including the maximum time that may elapse between the completion of processing and equipment cleaning (dirty hold time), when appropriate
• Instructions for the removal or obliteration of previous batch identification
• When appropriate, instructions fowrwdw.iwseabosfpshearmmab.cloimng and reassembling equipment to ensure proper cleaning
• Complete description of agents, materials, and equipment/apparatus to use for cleaning and disinfection, including dilution of cleaning agents used to clean equipment
• Disposal procedures for waste material and debris
• Instructions for storing equipment in clean and dry conditions
• Instructions for the protection of clean equipment from contamination before use
• Inspection of equipment for cleanliness immediately before use
Maintenance
Elements of a maintenance program should include a way to identify equipment with a distinctive name, number, or code. The equipment must be maintained in a good state of repair when in use, and where a potential for the contamination of the drug being fabricated or packaged exists, surfaces must be free from cracks, peeling paint, and other defects. Gaskets must be verified as functional, and the use of temporary devices such as tape is avoided. Equipment parts that come in contact with drugs must be maintained in such a manner that drugs are fabricated or packaged within specifications. Finally, records of maintenance documenting the performance of these activities must be kept.
Schedules and procedures (including assignment of responsibility) should be established for the preventive maintenance of equipment. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective. For equipment not requiring maintenance, the firm must be able to support its decision to not include the equipment in the maintenance program.
Equipment Change Control
A change control system should be in place to ensure that impact to cleaning processes or function is assessed, documented, and approved. Methods for verifying that a change control system is defined and implemented should include a way to verify that a documented procedure is in place. The procedure should require that changes are properly documented, evaluated, and approved by the quality function. The implementation/effective date of the change should be identified. Significant changes are assessed to determine if revalidation is necessary. A review of nonroutine maintenance, calibration, or nonconformance records can be used to determine whether changes to equipment have been made using appropriate change controls. Examples of changes that require evaluation and may require revalidation include:
• Changes to the cleaning procedure
• Changes in raw material sources
• Changes to product formulation
• Changes to the production process
• Introduction of new products, new cleaning agents or detergents, or changes to cleaning agents or detergents
• Modifications to equipment
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