Validation Questions
Question 1: When should a company validate/ revalidate cleaning procedures? When is validation not required?
Answer: Ref. Section 7.0 and 10.0 Companies should look at each situation individually and determine the need
for validation. Section 7.0 provides a basic template, which may be used as a starting point in this evaluation. The necessity to revalidate cleaning procedures should be determined under change control parameters – See
Section 10.0.
If routine verification procedures are used, these should be monitored to ensure that the procedure is in control. Companies should consider a periodic evaluation of cleaning procedures , which are subject to variation (i.e. manual
procedures etc.), as an additional precaution to assure that the procedures are still valid.
Question 2: When is it appropriate to use Prospective, Concurrent or Retrospective Validation
Answer:Ref. Section 9.0
Retrospective Validation of cleaning is not condoned by regulatory Authorities Prospective Validation is the ideal method of validation.
In situations where very few runs are manufactured in any given period and/or a business decision has been taken to release the next material manufactured after cleaning based on a high level of testing of the equipment (i.e. Validation level,) concurrent release of material may take place.
Question 3: What level of testing is needed after cleaning validation?
Answer: Ref. Section 5.3
The answer to this question depends on individual situations. Typically, companies perform visual inspection and take rinse samples to monitor the effectiveness of the cleaning in pre-defined intervals (time or number of batches).
If after validation company decides to perform always cleaning verification non-specific scientifically sound analytical methods may be used.
A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below:
1.)Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step.
2.)Take a rinse and/or swab sample (one liter of rinsing liquid is usually required)
3.)Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.)
4.)If the result meets the specification, proceed to specific (chromatographic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range – UV and specific derivatization – if these techniques
are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue)
and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the standard.
If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection.
5.)If TLC is not the appropriate technique, revert to HPLC or GC.
Question 4: What critical parameters need to be looked at during cleaning validation?
Answer: Ref. Section 8.2 for details
It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning
procedure should be covered.
Question 5: What number of cleans should be run in order to validate a cleaning procedure?
Answer: Ref. Section 9.0
A validation program generally encompasses three consecutive successful replicates. However, companies should evaluate each situation individually.
Question 6: Is it acceptable for a validated cleaning procedure to be continued until the analytical results demonstrate it is clean?
Answer: Regulatory authorities do not condone this practice.
When the analytical result does not meet the acceptance criteria an investigation to determine the possible root cause should be performed. If needed re-training of the operators should be performed and/or adjustment of
the cleaning procedure to solve the issue.
Question 7: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be dirty before cleaning?
Answer: Companies should have SOPs in place, which require cleaning to be performed immediately after production has stopped. This scenario should be validated.
However, if for some reason immediate cleaning is not always possible, companies should consider the effect of time on the material deposited on the equipment. It may be possible to ‘Group’ or ‘Bracket’ products, and validate a
worst case scenario.
Question 8: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be left clean before re-use?
Answer: Companies should have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place i.e. ensure that the equipment is adequately covered, closed from dust etc.
If the company feels that there is any risk of contamination during ‘idle time’ after cleaning, validation should be considered.
Question 9: Is it necessary to establish time limits for cleaning if equipment is not used frequently?
Answer: Please see previous advice to question 8.
Question 10: What is the maximum time allowed after cleaning with water as last rinse?
Answer: Equipment should not be left with water in it after cleaning. The last step of the cleaning procedure involve drying with solvent or flushing with Nitrogen, thus ensuring that there is no opportunity for microbial growth.
Question 11: Is it possible that a deterioration of equipment may take place over time, thus invalidating the original validation results?
Answer: Materials used to manufacture equipment for the pharmaceutical / chemical industry is of a very high standard. However, equipment materials used should be evaluated to ensure their durability over time as part of the preventative maintenance programme. The possibility of surface roughness and any possible effects that it may have on cleaning should be considered. Companies employing verification methods after validation should monitor
analytical data generated as part of this process.
Question 12: If a company has validated a worst case scenario (grouping or bracketing regime), should they also need to validate a ‘less’ worst case?
Answer: When grouping products and determining worst case situation scenario for validation, companies should determine whether or not the worst case being validated is one, which is appropriate for routine manufacture. For operational reasons it may be beneficial to validate a ”less” stringent cleaning procedure for some products.
Question 13: In a case of a dedicated plant with no degradants, is there a need to validate?
Answer: Ref. Section 7.0
Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need.
However, consideration should be given to the number of runs being performed prior to full cleaning.
Question 14: Should cleaning validation be part of a development programme?
Answer: While it is not a requirement of ICH that cleaning validation be performed during development phase the following should be considered:
If the equipment being cleaned after the development product in question is used to manufacture commercial product or product for human use for example clinical trials, it is essential to verify the appropriate cleanliness of the equipment prior to re-use.
Development of the Cleaning procedure for the product should take place at development phase for validation when the product becomes commercially available. The cleaning procedure validation should be performed or at least
should start with the process validation campaign.
Question 15: Is it necessary to include microbiological testing / aspects in the cleaning validation programme?
Answer: Ref. Section 8.1
Yes, if the following product needs to have a low microbiological load, also depending on the cleaning agent used, if there is any risk for microbiological contamination of the subsequent product (e.g. if water is used for final cleaning).
Question 16: Which analytical methods should be used in cleaning validation studies (is only HPLC -testing acceptable?) and to which extend should these methods be validated?
Answer: Ref. Section8.0 of this “Guidance on Aspects Document” Any analytical method suitable for its intended use could be used. In general limit tests are performed in cleaning validation studies which result in less stringent
validation requirements. (as outlined in ICH-Q2A and Q2B).
However, if a company decides to validate analytical methods, suitable for the determination of the residue over a certain range (e.g. decay-curve, to prove the success of cleaning during proceeding of a defined cleaning procedure consisting of individual cleaning steps) also less stringent validation requirements for e.g. linearity and accuracy could be established compared with figures typically required in the validation of API release testing methods.
Question 17: Do we have to wait for swab and rinse samples to be approved prior using the equipment for production?
Answer: During cleaning validation studies it is recommended to wait for completion of all planned tests prior to release equipment for further use (to be able to perform an investigation if tests fail). In routine operations (after validation has been completed) the release of equipment pending testing results (verification, monitoring status of the tests) could be done. Responsibilities and circumstances for using equipment pending release should be defined
within the company
Reference: GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS
