Cleaning Validation Considerations for Biopharmaceuticals
Today’s pharmaceutical companies are taxed with a great responsibility to ensure the safety of their products. To comply, they must adopt current good manufacturing processes (cGMPs) that prevent the potential for contamination of their products. Preventing contamination requires pharmaceutical manufacturers to ensure that their equipment is free from contaminants that could compromise the safety of their pharmaceuticals. Cleaning validation for drug manufacturers is strictly regulated and provides a guided process for verifying and validating the cleaning of all associated equipment and machinery.
Maintaining a pristine manufacturing environment has not always been priority-one for some pharmaceutical companies. Oversight or failures led to significant contamination of pharmaceutical products in the past. In 1988, for example, a manufacturer was forced to recall Cholestyramine Resin because it contained traces of pesticide. More recently, a European pharmaceutical company was forced to initiate a widespread recall of an HIV pharmaceutical product because it had been contaminated by ethanol. Contamination situations like these, expensive and potentially deadly, have led manufacturers and, of course, government regulators to pose the question: what, precisely, does it mean to be clean?
Creating a Protocol for Clean
From the pharmaceutical manufacturer’s perspective, cleaning refers to the removal of residues from previous product and cleaning agents. The genesis of these substances may be rooted in cleaning products like sanitizers or detergents. Cross-contamination may also occur by way of product previously processed by a piece of machinery. An earlier 1963 FDA regulation outlined that “equipment shall be maintained in a clean and orderly manner.” As instances of cross-contamination occurred, the FDA was forced to increase the specificity of its definition of clean.
The FDA has specifically described its stance on good manufacturing practices in Sec. 211.67: Equipment Cleaning and Maintenance of its regulations in association with finished pharmaceuticals.
In keeping with this regulation, each associated company must maintain cleaning and sanitizing schedules. Inspection must also be performed before equipment use and the company must maintain detailed records of its cleaning processes, inspections, etc.
The FDA requires pharmaceutical companies to employ a cleaning verification process. This is a quality control process that determines the effectiveness of cleaning processes needed for a cleaning event (i.e. proof that the cleaning is effective after every batch manufacturing). Cleaning verification invariably involves numerous steps. The company must submit analysis samples after the equipment’s cleaning has been completed. Quality control staff are required to complete the analysis and report their results to the manufacturing department or unit. The cleaning must be repeated until every sample collected from the manufacturing areas meets the acceptable residue limit (ARL). The analytical method employed by the company also holds a requirement to be specific and accurate. Ideally, if it is to be cost-effective, it should be fast, but never so fast that it sacrifices precision.
Cleaning validation is a company’s documented guarantee that the cleaning processes are performed reliably and consistently with the FDA’s cleaning validation guidelines. The validation process is a major part of GMPs. By validating the cleaning process, compliance with standard regulations and federal regulations can be ensured.
The Validation Plan
Pharmaceutical companies must employ a master plan for validation of their cleaning. The plan will outline member or team responsibilities. It will describe equipment, products, and procedures and include a test for acceptance limits (NOEL or No Observed Effect Levels). More recently the Pharmaceutical Industry is moving towards implementing ASTM E3106-18: Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation.
The validation plan should also include validated analytical methods, sampling procedures, cleaning processes, and change control and maintenance. Optimally, a company will form a validation committee that assigns roles like quality assurance and control; these members implement and ultimately must approve analytical methods, cleaning validation criteria and re-validation criteria and control changes to the master plan.
Cleaning Mechanisms, Agents, and Methods
The pharmaceutical company must outline its cleaning mechanisms, including its chemistry for contaminant removal. These mechanisms typically involve wetting, solubility, hydrolysis, dispersion, oxidation, physical removal or residues, and antimicrobial action. The company must specifically reference its cleaning agents, including water, organic solvents, surfactants, solvents, oxidants, and others. Methods must also be outlined and must describe how cleaning is to be accomplished. These methods might include soak, spray, and wiping. All these are components of the Master Cleaning Validation Plan.
Sampling and Analysis
As mentioned, the sampling and analysis of samples must fall within defined acceptance limits. Sampling reports should explain how the sampling is to be performed (i.e. swab and/or rinse). Analytical methods employed by quality control must be spelled out implicitly, in detail, and, of course, followed to the letter – or number.
Final Validation Report
The final cleaning validation report should supply the cleaning process design that references standard operating procedures. The report must include a justification for cleaning limits established in association with data inputs such as equipment surface areas, batch and dose sizes, and safety factors. If any part of the company’s processes or procedures are altered, the validation report must include their change control procedure. Procedures regarding emergency changes should also be included. When major changes are made to the processes, revalidation becomes necessary.
Pharmaceutical companies are obligated to comply with the FDA’s regulations or face penalties. According to the FDA, “Inspection findings that demonstrate that a firm is not operating in a state of control may be used as evidence for taking appropriate advisory, administrative, and/or judicial actions.” If inspectors find fault with the company, the company will be expected to address its deficiencies by providing corrective actions. These actions will be subject to monitoring and may include drug recall, the shut-down of the operation, and development of new procedures.
According to the FDA, “If an inspection report documents that one or more systems at the establishment is/are out of control, the inspection should receive an initial OAI classification. Issuance of a Warning Letter or taking other regulatory or advisory actions pursuant to a surveillance inspection should result in the classification of all profile classes as unacceptable.”
Inspectors have much to consider when examining each company and its breach or breaches. Companies can expect inspectors to consider whether the company has exhibited a pattern of failure before reviewing or approving its procedures. Inspectors will want to note if the company has demonstrated a pattern of failing to document its processes or failure to review. documentation.
Additionally, inspectors must note any contamination with microorganisms, contaminating chemicals, or dirt. They will note any failure in the cleaning validation process or failure to investigate its own discrepancies. Depending on the failures or pattern of failures witnessed, inspectors will recommend an action that may range from a warning letter to more serious repercussions.
Cleaning verification and validation are integral to the operation of pharmaceutical companies. The FDA has outlined regulations that must be followed or companies risk non-compliance. Non-compliance can result in warning letters, full inspections, monitoring, and even a shutdown of the operation. If a company’s products are found to be contaminated, a product recall will be initiated, and the company may face other punitive actions. Consequently, following the FDA’s regulations precisely is the only way to ensure compliance.
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