Questions and Answers about Cleaning Validation - Part 1
In March 2022, ECA Academy conducted an online training on cleaning validation - during which participants had many questions. Due to the large number of questions answered, we have split this post. Below you can find the first part of the questions answered by the speaker Robert G. Schwarz from FH Campus in Vienna.
All answers reflect the opinion of the speaker and are based on his experience.
1. Best practice documents: ISPE 'Guide to Cleaning Validation' is not mentioned - why not? It seems to contain a lot of practical and detailed advice.
It is also a recommendable best practice document.
2. Therapeutic macromolecules - "PDE limits may not be required": You still must be sure that (almost) all these APIs are degraded/de-natured and that they haven't found their way into nooks and crannies?
Yes, I agree. Full contact time and submersion is a must to apply a "degradation-strategy" for CV.
3. Do you suggest of using NOEL over NOAEL when determining PDE value?
I suggest using NOEL, because a desired effect of product 1 with patient A could be an adverse effect for patient B using product 2.
4. Regarding worst case parameters: 'Stickiness' or adhesive force could also influence difficulty of cleaning?
In a multi-purpose scenario, we use the most toxic substance for limit calculation but need to take into consideration cleanability of the different products. I recommend performing lab scale studies to determine the hardest to clean product.
5. Would 'visual clean' be a prerequisite for e.g., sampling or is it not considered at all anymore?
Yes, it is a prerequisite, although the limits of sampling methods used for analytical acceptance criteria could be higher. "Visual clean" is a general GMP-requirement.
6. Is a requirement of all piping being completely filled during CIP compatible with the requirement of turbulent flow?
Yes, the flow condition and the media volume stream must assure this. It should be part of the URS of the equipment and I recommend measuring flow velocity in piping as an IPC because it is a critical process parameter for cleaning.
7. When brushes are used Inspectors also challenge cleanliness of the brushes. What is the recommendation?
I would recommend using single use brushes or single use wipes instead of brushes. If possible, switch to an automated cleaning process.
8. Is it necessary to perform tests for detergent residue after a product batch, or is after e.g., a water-batch enough? Is it required to demonstrate a possible detergent-product interaction?
Yes, it is a requirement from Annex 15 of EU-GMP Guideline. I'd recommend having pre-rinse steps with tap water or PW and then using cleaning agents to avoid interaction with a major amount of product residues.
9. After the first 3 cleaning validation runs, how often must we revise the cleaning processes? Re-validation?
Risk based approach in VMP. This is also defined in cleaning validation report specific for the cleaning process, the equipment and the products. Usually, shorter frequencies at the beginning of routine cleaning (routine production) are advisable and elongen the frequency data based.
Heidelberg, Germany25/26 January 2023
Process Understanding - Statistical Process Control (SPC) as a tool to get there
10. Where can we find in the regulations that visual clean is not enough anymore?
Annex 15 of EU-GMP Guideline states that it is as not enough as a SOLE criterion. Visually clean should be done whenever possible (at every cleaning run).
11. Would it make sense to perform risk assessment on cleaning already during product development?
Yes, this makes perfect sense. Additionally, if I can perform lab scale studies with product at that stage it would be highly. Furthermore, a first estimation in a log-step scale of the toxicity could be performed when already having data available of comparable substances as part of legacy products.
12. Is it possible to cover manual cleaning only by risk assessment, if it is only manually cleaned not product/ indirect product contact equipment/ process aids?
Yes, from a regulatory point of view it is possible, because only direct product contact surfaces are needed to undergo cleaning validation according to Annex 15 of EU- GMP Guideline. BUT I'd recommend performing at least a risk evaluation for indirect product contact parts for non-steriles and include indirect product contact parts for aseptic processing in the cleaning validation.
13. Is the efficacy criteria also applicable to excipients?
Based on the fact that each excipients has its specific function (stabilizer for pH or osmolarity, preservative , ...) this needs to be taken into consideration in the risk assessment as well when focusing on interaction with residues. For the efficacy of the cleaning process, we need to consider that excipients could be the hardest to clean substances in the product matrix that may especially accumulate in cleaning processes within campaigns (batch-to-batch cleaning) or when using dedicated equipment.
14. Purity: How can you set purity requirements for excipients? I.e., Assay in Spec is only >85 %?
You need to know from the production process of the excipients what the remaining 15 % are consisting of. Usually this is hard to evaluate and therefore high purity is requested for excipients. Additionally, it is depending on the process step.
15. Is there a legal definition for dedicated equipment meaning?
No, at least I didn't find one even the term dedicated equipment is widely used in regulatory documents.
16. 3 CV runs should not be used anymore, it should be determined by risk assessment. What points should be considered in this RA when determining number of CV runs?
Risk basement with 3 runs initially and during first production runs intense sampling to get data and based on this the frequency of OCV is determined. Critical factors are the type of cleaning process (manual, COP, WIP, CIP in ascending criticality), is it a cleaning process for multi-purpose or dedicated equipment, which production step(s9 is the equipment used for and how critical are the substances regarding cleanability and toxicity.
17. Visual clean is not enough for dedicated equipment, correct?
Annex 15 of EU-GMP Guideline states that it is as not enough as a SOLE criterion. Visually clean should be done whenever possible (at every cleaning run)
18. How do you validate chromatography equipment?
Part of last talk - life cycle validation. No direct sampling possible in routine usage, so the number of cycles needs to be validated that includes cleaning validation. OCV only rinse sampling.
19. How do you set limits for bioburden for medical devices?
I'd recommend performing a risk-based approach taking the classification of the medical device into consideration as well as a (if applicable) subsequent sterilization process. This should also include endotoxins!
For IVDS the impact of any bioburden or toxin contamination needs to be taken into consideration regarding its influence on the result of the IVD-System and subsequent medical treatment of a patient.
20. Is there any guideline for excipients available?
IPEC-PQG ´Good Manufacturing Practice Guide, (www.ipec-europe.org)
21. How do limits differ for medical devices and pharma?
Standard Guide for Validation Cleaning Process used during the Manufacture of Medical Devices ASTM F3127-16, (www.astm.org)
22. Is riboflavin test acceptable for spray ball cleaning validation? Any alternatives?
It is acceptable for the spray pattern test to show full surface coverage in equipment OQ. To include the mechanical abrasion other substances that enhance the "stickiness (PEG, gelatin, ...) could be added for cleaning process development purposes. Any fluorescent substance will serve the purpose of riboflavin but riboflavin is the least human-toxic substance of the different substances (Na-fluoresceinate, Luciferine, …) that are, or better were, commonly used.
23. For medical devices: How extensive do extractables and leachables projects need to be? Required as a precursor to cleaning validation?
Mainly important for those medical device classes that get into the patient and even more severe stay there longer. Besides that, major topic is leachables from primary packaging material and after that extractables during cleaning process. So it is an interaction. For extractables I need a defined cleaning process and for the materials that potentially release extractables I need to consider this for cleanability.
24. Considerations for COP in washrooms and washers?
COP in washrooms are manual cleaning processes that are hard to validate. Low robustness and high variability demand extensive safety margins for validation cycles, usually for the CPP "time" or skipping the CPP "mechanics". For washers it is important to have distinct loading patterns and to verify that no segregation requirements are violated when using a COP process including equipment from different processes with different product residues. Sometimes even a change-over cleaning with an empty chamber cleaning run is necessary to fulfill these requirements.
25. In case pipes are only blown out with nitrogen. How can you take a rinse sample? Do you have experience on that?
Usually, it is taken at the final rinse step prior the drying with nitrogen. If it is only blown out with nitrogen and no "liquid" cleaning is performed it is possible to perform a solvent rinse with an adequate solution where the residues are highly soluble.
26. Swab solvent includes phosphoric acid due to recovery rate, is a special cleaning step necessary?
I'd recommend a rinse step with PW or WFI and measuring the conductivity as an IPC.
27. Some references are against the use of templates as there may be accumulation of contaminant under the template or the template itself may contaminate. What is your opinion?
I totally agree and would avoid it wherever possible. It is better to train the sampling operators to perform a worst-case sampling and sample AT LEAST XXXcm².
28. In addition to determining the recovery rate on the sampled surfaces (coupons), should there also be an individual determination of the recovery rate for those performing the swab sampling (how "well" is the swab sampling performed)?
I'd recommend to set-up a minimum required recovery rate (e.g., 75%) to be achieved by every sampling operator to be qualified but no individual recovery rates (could lead to calculation errors and deviations). This also reflects a worst-case concept
29. Could You pls tell best practice to sample CHT (MiBi sampling) of a conventional GL API reactor?
Based on my experience I'd recommend performing final rinse and contact plate sampling over MiBi-swab sampling due to usually higher recovery rates for those sampling methods.
30. How do you determine recovery rate for swabbing?
A recovery study determines the amount in percentage of a residue that was initially on the equipment that can be detected with an adequate sampling and analytical method. For detailed description see also:
31. Would you perform a recovery study using drug product or just the API, if you are working with e.g. capsule filling equipment?
I would use drug product because it represents the residues on the surface after cleaning better. Excipients could influence the recovery rate due to effects making the abrasion of the residues harder during swabbing which leads to a lower recovery. I'd always recommend sticking as close as possible to the "real process" when performing lab studies. This of course needs to be addressed in a risk assessment.
32. Why is it necessary to have the recovery rate before the analysis? Isn't it possible to adapt the result later?
If the recovery isn't determined as part of the "sampling procedure validation" which is part of the analytical method validation it could lead to are-validation of the analytical method based on the adoption of the sampling or even the analytic method itself. It is part of the system suitability test. of analytical method development.
33. If swab sampling and rinse sampling should be performed, which should be done first?
Usually when performing a final rinse sampling it is done first because the swab sampling interferes with the surface. If solvent rinse would interfere with the analysis of the swab, which is really rarely the case it can be switched supported by a risk assessment evaluating the impact of the swab sampling onto the solvent rinse.
34. What are best practices to sample hoses and production equipment brushes, especially for microbiology?
I'd use those, whenever possible, as single use. Alternatively, a rinse sampling can be performed for the hoses and for the brushes submerging them in a container and taking the media sample out of the container could be an option.
Heidelberg, Germany29-31 March 2023
The Validation Manager in the Pharmaceutical Industry
35. How do you set acceptance limits for detergents for TOC?
According to EMA "Shared facilities" Guideline long term toxicity data are only needed for product components. So for detergents we can use the LD50-value of the MSDS.
36. For detergent residue validation, is it necessary to perform an extra swab or rinse sampling, or is it sufficient to rely on the conductivity meter?
If the correspondence of concentration and conductivity is very high and could be shown with data this could work. I'd recommend drawing final rinse samples for conductivity because usually, based on my experience, you don't get exact results based on equipment design during an online-measurement compared to an offline-analysis. Alternatively, pH-measurement is a more robust process and could be used, if good correlation from pH to concentration of the detergent could be shown, cold be used as an IPC online solely.
37. If MACO calculation supported by efficacy data allows very high substance carry-over, would it be sufficient to support visual check with residue on evaporation data in order to verify cleanliness?
Only for OCV not for CV itself. But this is basically to fulfill regulatory requirements. I 'd also recommend using analytic methods om a significant lower frequency than checking visual cleanliness in combination with a solid qualification strategy for operators performing visual clean checks. Some companies also implement a 4-eyes-check with two operators to mitigate the risk of a subconscious bias leading to false compliant results.
38. Is toxicological evaluation required when changeover from one product to another in API production is practically biologically the same API family?
The fact that it is "practically biologically the same" needs to be evaluated in the toxicological assessment or at least in an risk assessment during clinical trial phase where this fact is even more (or at least earlier) important than for CV. Better alternative is a degradation- strategy avoiding HBELs.
39. What is you suggested changeover procedure during the product change-over -additional cleaning, testing?
Not necessarily if you have validated the campaign length properly but usually cleaning between batches and cleaning between products are two different cleaning processes with different scopes.
You will find the second part of this article in the next issue of the GMP Journal.
About the Author:
Robert G. Schwarz is a lecturer at the FH Campus in Vienna. He has 20 years of practical experience in aseptic processing, contamination control and cleanroom technology.