FDA 483 Observations Related to Cleaning in Pharmaceuticals | Common Issues and How to Prevent Them

Cleaning in pharmaceutical production is not only a standard procedure, it is also a regulatory requirement that enhances both product safety and quality. When cleaning is insufficient, the risk of contamination, cross-contamination or contaminated products can result in the distribution of dangerous drugs.

To confirm that pharmaceutical manufacturers comply with Current Good Manufacturing Practices (cGMP), the U.S. FDA provides routine inspection of manufacturing operations to confirm compliance with federal regulations under 21 CFR Part 211. When inspectors identify deficiencies in cGMP operations they issue an FDA Form 483 which identifies specific observations made during an inspection.

As seen in each year, cleaning and cleaning validation are two of the most significant areas of observation because they remain so complex and vital. This blog post will identify the top observations identified on FDA 483 forms in regards to cleaning, identify root causes of these observations and identify how Pharmaceutical Manufacturers can mitigate or eliminate these findings through effective processes and QA systems.

Understanding FDA 483 Observations

A Notice of Observations or Deficiencies (FDA 483) is a written notice given by the FDA to a facility when the agency believes that there are practices or conditions observed during the course of an inspection that could result in noncompliance with the provisions of the Food, Drug and Cosmetic Act. Although it is not an enforcement action with consequences, it can be treated as a serious notice from the agency to modify/take corrective action and implement preventative measures. If companies fail to address or repeat similar observations, they may expect to receive a Warning Letter, an Import Alert or a Product Recall.

The FDA examines cleaning procedures by determining whether a facility has validated and developed procedures to ensure that may not contaminate or cross-contaminate products.

Regulatory Requirements for Cleaning

The cGMP regulations that cover cleaning are found at 21 CFR 211 as follows:
§211.67 Cleaning and Maintenance - General requirements.
§211.63 Facility Design and Construction - Cleaning will be facilitated by the design and construction of facilities.
§211.182 Cleaning Records - general requirements for recording equipment cleaning.
§211.113(b) Control - Microbiological contamination of sterile drug products.
All cleaning procedures must have:
- A validated procedure that provides evidence of the effectiveness of the cleaning being performed.
- A log of all cleaning operations performed during a manufacturing run and documentation of the results of those cleaning operations.

Most Common FDA 483 Observations Associated with Cleaning

Let’s analyze the most widely cited issues and their likely causes.

1. Cleaning Procedures Not Validated or Not Adequate Documentation

Many firms receiving a 483 received a deficiency(s) due to their inadequate cleaning method(s) and failure to provide sufficient evidence that cleaning procedures were effective.
Typical FDA Language is as follows:
“Cleaning and maintenance methods and procedures of the firm are inadequate in that they do not prevent or minimize contamination or cross-contamination.”
Examples include:
- No verification of the removal of residue from earlier manufactured batches.
- No defined acceptance criteria for residue levels.
- No evaluation of the effectiveness of cleaning for all products and equipment.

Possible Root Cause(s):
- No documented scientific justification for cleaning limitation parameters.
- Lack of knowledge regarding product solubility and/or equipment design.

2. Lack of Written Cleaning Procedures

Some facilities still operate on verbal agreements and informal conversations regarding cleaning and maintenance.
Typical FDA Language is as follows:
“A written cleaning and maintenance process did not exist or is incomplete.”
Examples include:
- SOPs that do not contain cleaning instructions listed in sequence.
- A lack of defined cleaning agents, concentrations and times of contact.
- No procedure for verifying the cleaning or inspecting cleaning.

Possible Root Cause(s):
- Poorly written documentation.
- Not enough knowledge of regulatory expectations.

3. Inadequate Cleaning Validation Studies

Cleaning validation studies are utilized to demonstrate that any residual active ingredients, cleaning agents or microorganisms appear at acceptable levels. The FDA frequently identifies failings in the design and/or conduct of cleaning validation studies.

The following wording from the FDA typifies how they would describe these issues: "...the cleaning validation study failed to demonstrate that the cleaning procedures could reliably remove all residue to below the established limit(s)."
Some typical examples include:
- Cleaning validation studies conducted only on a limited number of products rather than the complete range of representative products.
- Selection of non-worst-case products (highest potencies, greatest challenges for cleaning, etc.) for study.
- The absence of cleaning verification studies (swabbing or rinsing) for residue recovery.
- Use of unvalidated analytical techniques for establishing residue detection.

The root causes for these types of cleaning validation study failures are:
- Insufficient planning of cleaning validation studies.
- Lack of adequate scientific justification for methods and acceptance criteria.

4. Cross-Contaminated Product Risk from Equipment Design or Maintenance

The FDA frequently identifies that the design and/or maintenance of equipment contributes to the risk of contamination to products.
The following wording from the FDA typifies the types of issues the FDA will identify regarding equipment: "...the equipment is not of an appropriate design to be effectively cleaned or maintained."
Some typical examples include:
- Chemical or other material that is accumulated in dead leg of pipeline(s) or other crevice(s).
- Leaking gaskets, valves or similar parts of your equipment that are causing contamination to cleaned surfaces.
- Using non-dedicated equipment and not validating the procedure for cleaning between products.

Root cause for these types of cleaning validation study failures are:
- Using multi-use/transfer equipment without risk assessment(s).
- Lack of use of hygienic design principles when selecting your equipment.

5. The Absence of Cleaning Records

Many observations noted in facility's inspection are related to missing required documentation/recordkeeping. Complete, contemporaneous and traceable documentation pertaining to Equipment Cleaning and Use Logs should be maintained by all FDA-regulated companies.

Common compliant statement from FDA inspectors: “Equipment Cleaning and Use Logs did not have all of the required entries, were not filled out correctly and/or were not up to date.”
Examples include:
- Some entries are missing (probably, operator's initials or date cleaning was completed).
- The order that was written on the Equipment Cleaning and Use Logs does not match the way that the equipment was actually cleaned.
- Cleaning logs do not tie back to any Batch Records.

Root Causes:
- Poor Data Integrity practices.
- Staff are not properly trained to follow up on Good Document Practices (ALCOA+).

6. Microbial Contamination

Microbial contamination of any equipment used in manufacturing sterile products is one of the most serious findings during an FDA inspection of a facility that manufactures sterile products.

Common compliant statement from FDA inspectors: “Failure to retain sterile Equipment Cleaning and Disinfection Procedures for equipment that is used in sterile operations”.
Examples include:
- Growth of microorganisms on the surfaces of tanks and transfer lines after cleaning.
- Where the contact time of the sanitizing agent or sanitizing agent was inadequate.
- Use of dirty cleaning tools (for example, mops, rags) without properly disinfecting them before reuse.

Root Causes:
- Sanitizing agents were ineffective and sanitizing agents had insufficient contact time with the equipment surfaces.
- Lack of environmental monitoring feedback into the Cleaning Program.

7. Lack of Periodic Revalidation or Cleaning Effectiveness Monitoring

The FDA expects companies that develop cleaning and sanitization procedures to periodically review and update these programs to ensure that cleaning continues to be done effectively.
As an example, the FDA states:
"Cleaning validation should be periodically evaluated for continued effectiveness."
A few examples of this would be:
- No trend analysis performed for swabbing and rinsing results (e.g., using swabs/rinses that were not tested over a certain period).
- No routine revalidation is performed when modifying equipment or introducing new products.

Additional possible root causes for these types of findings are:
- Static cleaning verification processes; and
- The failure of the cleaning verification processes to include cleaning validation data in the site's quality review for continuous quality improvement efforts.

Strategies to Prevent Cleaning-Related 483 Observations

Developing cleaning related citation Preventative: a comprehensive strategy for Contamination Control using Science, Records and Continuous Improvements is the best way to create a culture of Compliance with Cleaning Regulations.

1. Develop Standard Operating Procedures for Cleaning

• Responsibilities of who is responsible; frequency of cleaning, procedures for cleaning should be clearly defined.
• The cleaning agents should be validated to include concentration, contact time, etc... The inspection and verification methods should also be included.

2. Build a Controlled Cleaning Validation Program

• Select the worst-case products for cleaning based on Toxicity, Potency and Solubility.
• Establish Acceptance Criteria scientifically justified, e.g., 0.001 dose method, 10 ppm limit.
• Validation of analytical and sampling recovery method; Visual inspections used to validate acceptance.

3. Ensure that the Design of the Equipment Supports Cleanability

• Utilise equipment that has Smooth, Drainable Surfaces with Minimal Dead Legs.
• Utilise hygienic fittings with regularly maintained seals and gaskets.
• Validation of Clean-In-Place and Steam-In-Place systems.

4. Maintain Cleaning Records that are Complete

• Document who cleaned, when they cleaned and what they cleaned.
• Link the cleaning records with Batch Manufacturing Records.
• Regularly review logs as part of QA Oversight.

5. Train Personnel Thoroughly

• Have a formal training program for the cleaning process, how to complete the cleaning documentation, and cleaning safety practices. 
• Re-train on the cleaning processes and documentation when new SOPs are put into place or when the cleaning procedures change.

6. Implement Microbial and Chemical Monitoring

• Microbial sampling includes surface samples and rinsing (i.e., wipe down) samples.
• Cleaning residual tests are performed using validated analytical methods (HPLC, TOC).
• Results are trended to identify process drift and/or new risk.

7. Revalidate and Continuously Improve

• Regularly reassess cleaning effectiveness, especially following any process or product change.
• Annual product quality review (APQR) will include cleaning data.
• Promote a culture of pre-emptive improvement instead of reactive correction.

Case Example: Learning from an FDA 483 Observation

Observation: “The firm failed to establish scientifically sound cleaning validation to ensure removal of active residues from shared equipment.”

Root Cause: Although cleaning validation was validated against a representative product, the cleaning validation used was not based on a representative sample of the most "difficult to clean" active ingredients.

Corrective Action: The firm revised their validation protocol to identify worse case products and begin using a residue tracking program where trends can be monitored.

Preventative Outcome: Improved Process Understanding, increased compliance verified during the next inspection cycle.

FDA 483 cleaning deficiencies are among the frequent critical deficiencies noted in pharmaceutical inspections. Cleaning deficiencies can indicate documentation, validation, isolation and contamination control issues.

Cleaning's role in industry is about more than regulatory compliance — the cleaning program is directly tied to safety and confidence in the product for the patient. A thorough cleaning program encompasses standard operating procedures with detailed written procedures; validation of the cleaning process; continuous monitoring; and a corporate culture of quality ownership — all of which address the root causes of cleaning failure and foster a lasting sense of confidence by regulators.

Frequently Asked Questions (FAQs) on FDA 483 Observations

Q1. What is an FDA 483 observation?

Answer: An FDA 483 observation is a notification issued by the FDA after an inspection on what they believe are examples of possible GMP (Good Manufacturing Practice) violations.

Q2. Why does the FDA focus on cleaning?

Answer: The FDA has an interest in cleaning because poor cleaning leads to contamination and cross-contamination during manufacturing and use of drug products.

Q3. What are common cleaning-related 483 issues?

Answer: The most common 483 issues related to cleaning result from having unvalidated cleaning procedures, no Standard Operating Procedures (SOPs), limited documentation and microbial contamination.

Q4. What is cleaning validation?

Answer: Cleaning validation assures cleaning procedures are capable of consistently removing residues to acceptable limits.

Q5. How often should cleaning be revalidated?

Answer: Cleaning revalidation should occur periodically as well as when there are changes to the equipment, product or process.

Q6. What are worst-case products in validation?

Answer: Worst-case products refer to those that would be the most difficult to clean or have the highest level of toxicity/potency.

Q7. What is the role of documentation in cleaning compliance?

Answer: Docs are the primary way companies demonstrate how products are made and adhere to GMPs. Proper documentation provides a means of showing traceability to products and proves adherence to GMPs.

Q8. How can firms prevent 483 observations?

Answer: Companies can reduce the incidence of 483 observations through a combination of comprehensive validation, ample training of employees, monitoring of the process and periodic reviews of the process.

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