Cleaning validation

Question 2

The primary cleaning validation guidance’s that we find within the European Union:

Answer 2

• EMA guideline on setting health‐based exposure limits
  
  • EMA guidance that can be found within EudraLex volume 4 Annex 15 qualification and validation
  • EudraLex 4 chapters 3 and 5 premises and production.

Question 3

What does Annex 15 cover for cleaning validation?

Answer 3

• details the requirements for qualification and validation of a cleaning method
  
  • gives examples of how to plan for the validation program
  • how to document your programme
  • how to complete and maintain your validation program for your cleaning methods.

Question 4

What can you tell me about Annex 15 risk based approach to cleaning validation

Answer 4

A quality risk management approach should be used for validation activities with risk assessments repeated as required in the light increased knowledge and understanding.

This risk‐based approach based upon science and process understanding allows us to generate a targeted plan and to justify the plan based upon specific knowledge and data for example:
* do some products we are working on have very specific characteristics that make cleaning more difficult?
* Is the cleaning method reproducible?
* do we have data to support this?
* How do we justify a worst‐case molecule or a worst‐case cleaning condition for example the products which is difficult to clean that’s been left lying on equipment for a prolonged period of time?

These are common occurrences within our industry and all need due consideration.
The use by the industry and the acceptance by the regulatory agencies, of a risk‐based approach gives us the opportunity to justify and defend what we choose to do based upon good data, good knowledge, good science.

Question 5

What else does Annex 15 summarise for cleaning validation?

Answer 5

• common cleaning practices across the industry and deals with key product contact parts and, Product residues, cleaning agents and detergents and also covers resultant microbial contamination.
  
  • the criteria for ‘’Time” between usage and cleaning, dirty hold time,
  • it also discusses the amount of time equipment will still be considered as clean before next use, clean the hold time.
  • Annex 15 also discusses the use of a worst‐case molecule. This is the molecule, chemical, or products that is the most difficult clean and potentially the most toxic, that we can use as a model to support cleaning of all other products or at least as a minimum to all other related products.

Question 6

What does EudraLex Volume four chapter 3 say about dedicated facilities?

Answer 6

• Historically it was always the case that if you were manufacturing hormones, some cytotoxics or any beta‐lactam antibiotic then a dedicated facility would be required.
  
  • This is not now automatically the case and the pharmaceutical industry has the opportunity to justify how it controls containment, cleaning and validation, that would support potentially a multiproduct facility.
  • Whilst this is achievable on paper do not underestimate the amount of work this would require to justify.
  • However, the use of science and Data driven risk‐based decision‐making has given the industry and opportunity to discuss to justify what we do.

Chapter 3 specifically states the dedicated facilities would be required under certain conditions and these are
* those products or processes that cannot be adequately controlled by operational and or technical measures
* the scientific data that we have available does not support a clear threshold value, Such as the case of highly sensitising material
* the toxicological review results in acceptance criteria which is unachievable by available analytical methodologies. Four example the level quiet is below the validated level of detection in the method.

Question 7

What do current guidelines propose for cleaning validation limits?

Answer 7

• should be based upon a risk evaluation per product and not on a generic carryover level
  
  • Should be based upon a permitted daily exposure (a health‐based calculation) should be determined on a case‐by‐case basis and justified, for example is it toxic? Is it a carcinogen or a sensitizer?
  • should be calculated considering the route of administration and how that impacts the pharmacology / bioavailability

Question 8

What are health based exposure limits?

Answer 8

The limit is based upon the no obvious effects level multiplied by a weight adjustment, For example 70 kg for average man. Divided by five modifying factors.

F1 is a modifying factor between 2 and 12 they can be used to account for extrapolation between different species the preclinical data. This allows us to weight the data based upon our knowledge and understanding of the preclinical modelling relevance.

F2 the modified factor of up to 10 to account for variability between individuals. This will be based upon existing knowledge of variable exposure caused by any contributing factor such as with the route of administration or the bioavailability of the drug concerned.

F3 this is another modifying factor of 10 to allow for repeat dose toxicity. Normally these are studies of short duration but of multiple dosing. For example, if you are assessing carryover into a product maybe dosed four or six times per day then the potential exposure to the patient to a cross contaminant present in that product Will be higher than if the contaminated product was dosed once per day.

F4 is a factor of 1 to 10 that maybe applied if there are cases of severe toxicity such as neurotoxicity or carcinogenicity.

F5 is a modifying factor that maybe applied if the no effects level is not observed then the LOEL is used in its place.

All the modifying factors must be justified in a documented risk assessment however you should remember that the modifying factors are there to allow you to use the calculation to ensure safety, so they all add a safety margin in effect.

Question 9

What should be in a HBEL summary report?

Answer 9

• The company name should be specified
  
  • The address to which the risk assessment applies should be specified
  • The expert or expert’s names and signatures and date of review should be prominently included
  • There should be a reassessment date included within the report
  • The chemical name or related names of the molecule or molecules being assessed should be specified

This should then follow a series of statements and answers such as:
* Is the product genotoxic?
* Is the product repro toxic?
* Is it a known or suspected carcinogen?
* Can it be a sensitising agent?
* The basis for the health‐based exposure limit as permitted daily exposure limits as previously mentioned.
* The dose of which a critical effect has been observed.
* The dose at which the health‐based exposure limits is based, the planned expected Minimum therapeutic dose.

Finally, a comprehensive reference list citing sources used in the assessment.

Question 10

Cleaning validation Analytical method selection

Answer 10

• Is the Analytical method you’ve chosen fit for that purpose?
  
  • Is it appropriately sensitive and validated to detect the levels required in cleaning qualification?
  • These are hugely important aspects that need to be dealt with because a poor choice of method or poor sensitivity is inacceptable.
  • The level of quantification and detection that does not meet the requirements that you set in your clean acceptance criteria will make the method useless for its intended purpose.
  • Secondly you have to choose the sampling techniques you’re going to use and whether those methods are compatible with the analytical methodologies you have chosen?

Question 11

Cleaning validation sampling

Answer 11

The two main sampling processes used currently are rinse samples and swab samples. Obviously whichever sample technique you use you need to justify and document.

Question 12

Discuss specific versus non specific cleaning validation testing methods

Answer 12

There is lots of discussion around specific versus non‐specific testing methods.
* It is true that specific methods such as HPLC are more expensive and more time‐consuming than the non‐specific methods such as total organic carbon (T0C).
* However specific methods provide the accuracy of data that is required to support cleaning verification and qualification especially in a multiproduct facility.
* If you use a non‐specific method in a multi‐product facility what does this actually tell you?

It tells you that you have contamination it does not tell you is that contamination was the last product or the penultimate product, what about before that. It is a build‐up of residue that has finally tripped your TOC limit?
* It does not help an investigation as to why your cleaning has failed.

Whereas HPLC provides accurate data for the molecule or markers you’re looking for and when failure occurs it facilitates a thorough and accurate investigation.

Question 13

What is the purpose of neutalising agents?

Answer 13

Neutralising agents will be utilised to counteract any chemical disinfectant that may be present and at the discretion of the microbiologist any contamination, or colonies, isolated maybe identified. This decision is often based on intended use of the potentially contaminated product.

Question 14

What should your cleaning validation bioburden limit be?

Answer 14

The bioburden should be no higher than the control limits that are set from the water that is used for the final rinse of equipment. Also, in facilities where you have a good microbial assessment program already in place and
you have knowledge of the local microbial Flora that exist within your facility then you should be able to demonstrate specific activity of the cleaning agents against named organisms commonly occurring in your facility.