This Cleaning Memo expands a discussion of Health Canada’s Cleaning Validation guidance (GUI-0028 June 29, 2021) to cover topics other than worst-case products in a grouping approach (which was covered last month). Specifically addressed are many topics that may help you design, audit, and/or improve your cleaning validation program and associated documents. Realize that many are not necessarily requirements, but represent issues that should be considered in evaluating your program (and most likely will be issues that regulatory agencies might look at in an inspection). I have added my “topic heading” for each separate item, along with the “section” number for each citation.
Validation Maintenance
Here is the text from Section 7.3.4. These are major things that may require special attention once initial cleaning validation is done.
“Areas of special concern, in terms of on-going monitoring, include:
a) products with low HBEL values which are generally more hazardous products
b) products for which visual inspection cannot be used to estimate cleanliness of the equipment, meaning HBEL derived residue levels cannot be visually detected
c) equipment and products with a history of failure or highly variable testing results during verification and qualification testing
d) manual cleaning processes
e) locations or surfaces that are difficult to access or clean
f) equipment which cannot be appropriately visually inspected”
Change Control
Here is the text from Section 7.3.1.2. These are major things that may require special attention related to possible or actual changes to your cleaning validation activities.
“Changes that may potentially impact cleaning process qualification/validation include:
a. new products
b. changes to the cleaning process
c. changes in the formulation and/or process of products
d. raw material changes (e.g. change in impurity profile or physical properties)
e. new cleaning agents and/or changes in cleaning agent formulation
f. significant equipment changes or new equipment
g. lot size or campaign length changes
h. changes in analytical procedures or sampling method or materials
i. changes to cleaning limits, which might happen upon periodic review of the
data which form the basis of the HBEL”
Criticality of Recovery Studies
Here is the text from Section 8.3 discussing importance of recovery studies. After the text I have added commentary related a possible misapplication of a phrase used in that text.
“Recovery studies demonstrate that the sampling and analytical methods can adequately measure residue that may be present on equipment surfaces. Such studies are performed by spiking material coupons with the residue under consideration at low levels representative of amounts after cleaning,
then sampling the residue according to the applicable method. Testing results should then be compared with the actual quantity spiked onto the coupon.”
Care should be used in interpreting what “low levels representative of amounts after cleaning” means. My general approach is that this is an amount representative of the cleaning validation limit (in mcg per square centimeter). If you perform recovery studies at even lower amounts (closer to the measured residue amounts), you could run into problems because the amount recovered may be below your analytical method quantitation limits, meaning that you couldn’t actually calculate a recovery percentage. Furthermore, at this lower values the “plus/minus” of the analytical method accuracy becomes may be wider. An extreme case of this is when your actual measured values are below the detection limit, meaning that recovery percentages cannot be calculated at all.
Visual Inspection
Here is the text from Section 9.1.2. These are items applicable to both routine visual inspection and visual inspection to determine that HBELs are being met.
“Establish procedures detailing how visual inspections are to be conducted. Include clear instructions with respect to:
• ensuring equipment is dry
• disassembly instructions
• use of an appropriate light source and lighting conditions
• how to assess difficult areas, such as the bottom of mixing blades”
Swab Sampling
Here is the text from Section 9.2.1.1. These items apply to swab (or wipe) sampling (but could also be considered for rinse sampling).
“Conduct swab/wipe sampling on areas determined during the risk assessment and specifically on identified hardest to clean areas. In addition, consider taking representative samples of large surfaces. Clearly specify hardest to clean areas in relevant protocols. The choice of swabbing locations should be justified with appropriate supporting data.”
Selecting Hardest to Clean Areas
Here is the text from Section 9.2.1.2. These are factors that may affect that selection process.
“Consider the following when determining hardest to clean areas:
a) accessibility
b) equipment geometry
c) potential for residue accumulation
d) material of construction”
Setting Final Cleaning Limits
Here is the text from Section 10. This applies to setting what is called “final cleaning limits” in relation to the HBEL limit.
“The amount of residue allowed on equipment and/or a process train after cleaning is referred to as a maximum safe carry over limit. This limit is determined by calculating how much of the active substance of the first product made could safely be carried over into the second product (after the clean) such that the maximum daily dose of the second product doesn’t contain more than the HBEL of the first product. When you take into account the surface area of the equipment and any other safety considerations, the preliminary swab or rinse limits can be calculated. The final cleaning limits chosen should not exceed this value.”
Historic Cleaning Limits
Here is the text from Section 10.2. This applies to dealing with “historic cleaning limits” when calculated limits are changed upward.
“Consider establishing alert limits in the event that HBEL derived cleaning limits are significantly higher than historic cleaning limits (for example, 1/1000th of a dose and 10 PPM). Cleaning procedures that are capable of achieving better limits than those derived from HBELs should continue to do so. Note that
cleaning limits must also continue to meet the visually clean criteria.”
Note that (in my opinion) the Health Canada guidance is one of the better (and more comprehensive) regulatory guidance documents on pharmaceutical cleaning validation. For those of you newer to cleaning validation, I suggest this document is a good starting point for understanding a regulatory perspective, and is certainly more useful as a good overview as compared to the much older 1993 FDA guidance (although I would be careful not to neglect the FDA document).
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