The increase in warning letters issued by the FDA over the past two years underscores the need for pharma companies to consider running mock FDA inspections or audits, to ensure they will not run into the same kinds of problems as companies that have already received these warnings.
For most companies, that extends particularly to refining their cleaning validation programs, and incorporating worst-case scenarios into their assessment processes.
There are many steps in the process of a mock audit. In this article, we’ll focus primarily on how to identify worst-case products for cleaning validation, which is one of the most common places in which FDA identifies violations.
The scope of the FDA warning trend
In 2023, the U.S. FDA issued 180 warning letters to drug and biologics manufacturers in fiscal year 2023. Some 51 warning letters have been issued by the agency in the first quarter of 2024.
These warnings (issued by the FDA’s Division of Pharmaceutical Quality Operations) typically address the need for appropriate improvements in cleaning validation programs. They summarize significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals, under Title 21 of the Code of Federal Regulations parts 210 and 211.
The specific violation observation is written as follows:
Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst case:
• drugs with higher toxicities
• drugs with higher drug potencies
• drugs of lower solubility in their cleaning solvents
• drugs with characteristics that make them difficult to clean
• swabbing locations for areas that are most difficult to clean
• maximum hold times before cleaning
Mock inspection basics
A mock FDA inspection or audit is a process for companies regulated by the FDA to determine how well they comply with FDA regulations — and to prepare themselves for actual FDA inspections. By conducting mock inspections, companies can understand any potential problem areas and to deal with those problems before they are noted in a real inspection.
Worst-case products for cleaning validation is an area that comes up very often in warning letters issued by the FDA. In assessing the risks attached to so-called worst-case products, companies have a better idea of how specifically to validate their cleaning procedures.
Risk assessments ensure that new products or changes in manufacturing processes are properly understood in the context of cleaning validation. To understand and identify worst-case products — and to create cleaning processes that will pass FDA inspections — several steps must be followed:
- risk identification
- risk evaluation and prioritization
- worst-case product selection/customized cleaning procedures
- ongoing monitoring
- implementing the plan
Let’s take a closer look at each step.
Risk identification
Here, an organization identifies products which, because of their properties and characteristics, may pose the highest risks for cleaning validation.
Let’s use the example of a pharma company that produces solid oral tablets and oral liquid products. In this case, a company’s risk assessment team would gather information on various products, focusing on factors like toxicity, potency, solubility and complexity of the drug formulation. By this we mean:
- High-toxicity drugs: Products with a narrow therapeutic window and potential severe patient impact from inadequate cleaning.
- High-potency drugs: Products that require very small doses, which to prevent cross-contamination make thorough cleaning crucial.
- Low solubility drugs: Residue accumulation may result from products that are characterized by low solubility in cleaning solvents.
- Complex formulations: Residue adherence is a likely consequence of drugs with complex formulations or excipients.
Risk evaluation and prioritization
Based on data collected in the first step, identified risks are evaluated and prioritized to understand which products should be treated as worst-case scenarios.
High-toxicity and high-potency drugs, for example, may be assigned high priority because of potential patient safety implications. Similarly, low solubility drugs could be categorized as high priority because of challenges faces in effectively removing residues during the cleaning process. Complex formulations, on the other hand, might have a moderate priority, depending on the product’s impact on cleaning.
Worst-case product selection/customized cleaning procedures
In this step, products with the highest risk scores are selected as worst-case products for cleaning validation process for their specific manufacturing equipment. These products must go through rigorous cleaning validation studies to ensure that the cleaning procedures are effective and can consistently remove residues.
For each worst-case product, a team must develop and validate cleaning procedures based on the specific challenges posed by the product’s properties. This might involve adjusting cleaning agents, cleaning cycles, or new cleaning equipment.
Ongoing monitoring
After the worst-case products are identified and cleaning processes are validated, it’s important to continually monitor the factors that can affect a validated cleaning process. Regularly updating your research ensures that the cleaning process is well-controlled. This monitoring extends to having procedures in place to incorporate new manufacturing equipment and new products, so that your worst-case groupings remain valid.
Implementing the plan
Once you’ve established your worst-case scenarios and appropriate processes for validated cleaning, you need to put what you’ve learned to work.
In terms of risk assessment and prioritization, this means creating a detailed risk assessment procedure to identify worst-case scenarios arising from drug properties, cleaning methodologies, and microbial vulnerabilities. Customized cleaning procedures must be established and validated according to to the specifics of each worst case scenario. This may potentially involve modifying solvents, cleaning agents and cycles.
It’s important to have visual Inspection and analytical testing to make sure that you have accurately verified levels of cleanliness that will mean FDA requirements, particularly for drugs that produce residues that may be challenging to clean.
Equipment and facility controls will need to be strengthened, to reduce the possibility of cross-contamination when dedicated equipment is used for high-risk drugs. This will require stringent environmental monitoring protocols to manage microbial threats.
Finally, it’s essential to maintain meticulous records of the entire cleaning validation process, including risk assessments, protocols and outcomes. This records-keeping will make it considerably easier to present transparent and precise reporting to the FDA or any other relevant regulatory body.
There are many different ways to create a mock audit to prepare your organization for an FDA inspection, and reduce your chances of receiving a warning letter. For the purposes of validating cleaning processes in your manufacturing operations, this somewhat specialized overview may keep you in the FDA’s good graces.
