Typical Cleaning Records Produced by Pharmaceuticals Manufacturing Plants
One of the most stated rules in GMP is “You cannot test quality into products. You must build it in at each step in the entire process.” This statement is especially true with regard to effective cleaning and prevention of cross-contamination in products. No amount of laboratory testing can substitute for prevention. The cleaning records, if completed correctly, should verify that each item of equipment in contact with product was cleaned:
- Using validated written procedures
- By trained employees
- Prior to use and stored correctly as per its status tag
There must be evidence, via inspection and monitoring records, that the equipment was clean and free from contaminants when processing commenced. It also must be recorded what previous product was processed in the equipment prior to the current batch.
According to US FDA CFR 211 – Subpart J-Records and Reports, Sec. 211.182 Equipment cleaning and use log.
“A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.”
Cleaning records are critical in a manufacturing operation. They are needed to:
- Provide evidence that equipment has been cleaned and checked before use
- Demonstrate that cleaning was done in accordance with SOPs
- Provide traceability and help in problem solving should a product prove to be contaminated
This is why equipment must have status tags stating “Clean” or “To be cleaned”. The GMP rule is to never use equipment unless it has a “Clean” status label attached, and has been inspected as clean.
Status tags and cleaning logs
Status tags are essential for communicating to all operators the cleaning status of equipment and rooms. This is especially important when different shifts are sharing equipment.
The images on the right are examples of a status tag and an equipment cleaning record. Each requires the date of cleaning, the name of the previous product and the name of the person who did the cleaning. The status tag clearly shows the cleaning status.
Simple cleaning logs are also essential to ensure that each cleaning task is performed correctly. The logs may detail:
- The area or piece of equipment being cleaned
- The cleaning equipment that is to be used
- The frequency of cleaning
- The responsibilities for the cleaning
Cleaning logs also allow for personnel signing that the cleaning has been performed, and perhaps in some cases, verifying that the cleaning was adequate.
The most important requirement of FDA 21 CFR 211.182 Equipment cleaning and use log is that each item of common use equipment must have an individual log that shows batch traceable cleaning history that is independent of the batch record.
How clean is clean?
A commonly-asked question is “How clean is dean?”
The answer is not straightforward. Company SOPs will specify the definition of dean, and appropriate acceptance criteria or limits. Generally, “how clean is clean” depends on a number of factors, including:
- The method of cleaning
- The nature and use of the equipment being cleaned
- The type of products being manufactured (e.g. injectable products, creams)
Some criteria for cleanliness can be:
- Visually clean
Visual inspection should always be used irrespective of other methods employed. Visual inspection should occur both post-cleaning and again before next use of the equipment.
- <0.1% detected
This limit is sometimes used as a default limit because it is less than 1/1000 of the previous active chemical in the next batch.
- Certain per million detected
This limit is similar to the <0.1% limit. A general guide for this limit is not more than 10ppm carryover to the next product.
- No product detected
Sometimes this limit is used when the allowable carryover of residue is higher than the limits of the analytical method being applied.
- No microbial activity detected
This limit is applied to microbial residues post-sanitation. While there is no specific limit required in regulations, the limit chosen should reflect that product risk. For example, for sterile products the limit is nil, while for tablets it may be higher.
Issues in equipment cleaning validation
Other issues to consider when validating equipment cleaning include:
- Using the active ingredient as a marker
- Considering all components of the product (not just the active)
- Ensuring that the analytical detection methods have been validated
- Determining the detection level of the test
- Determining whether endotoxins are objectionable contaminants
- Considering the effects of the presence of degradation products
- Considering the effects of cleaning/sanitation agent residues
- Determining different cleaning procedures for different products