Validation - Revision of Annex 15: How does the Industry see the Changes? - Results of an ECA Survey

Recommendation

23-25 April 2024

Cleaning Validation AND Pre-Course Workshop: Impact of Annex 1 Revision on Cleaning Validation - Live Online Training

With the publication of a draft on the revision of Annex 15 at the beginning of February 2014, changes in the area of validation/qualification were to be expected. Even then, the ECA Academy started an industry survey (Validation - Revision of Annex 15: Industry's "problems" - Results of an ECA Industry Survey). Now the final document is published and the changes will become valid on 1 October 2015. But how does the industry see the new requirements?

A total of 53 people took part in the survey, the majority of which answered all the questions. Almost 50% (49.0%) of the participants in the survey work for companies with more than 500 employees while 40.9% work for companies with more than 101-500 employees.

A total of 61.2% of the participants are employed in the pharmaceutical industry. 16.3% of the them work in the API industry (chemical API and biotechnologically produced API), for further distribution, see Figure 1.

Figure 1 Which products do you manufacture in your company?

25% of the participants that specified their role in the company work in the "quality" sector. 21% work in validation and the remaining participants are from a range of sectors (development process, various manager functions, etc.).That is all as far as demographic data is concerned.

It is rather surprising that the subject of active substances was addressed in the final revision. And in this regard, the first question was: How do you assess the statement that Annex 15 can optionally be used as a supplement in the area of active substances without additional requirements in the EU Guidelines Part II? 1/3 (34%) of the participants consider Annex 15 to be a positive supplement to Part II. For 1/3, it is not clear and just under 1/4 (22%) find that Annex 15 should also be completely applicable to active substances. 10% do not consider Annex 15 necessary in the area of active substances. 

The second question dealt with the subject of conditional approval: Will you use the option of conditional approval to the next stage in case of deviations with a documented assessment?
More than half of the participants (54.2%) will use this option, just as they did in the past. Almost 1/3 (29.8%) will accept this approach only in "exceptional circumstances". 14.6% will use it even more frequently than in the past. Only 2.1% will not allow this approach.

With regard to question 3 ("How do you assess the fact that FAT and SAT are only "could" options?") 68.8% regard it as a good idea that the tests are only optional. Yet almost 1/5 (18.8%) consider these tests mandatory. For 10.4% it is not clear what it is about. 2.1% do not consider the tests to be necessary.

50% of the participants assessed the option of combining qualification stages (IOQ, OPQ) in question 4 as a good idea and will also do so. For just under 1/3 (29.2%) it is already common practice. 12.5% would not like to use combinations and for 8.3% the approach is not clear. 

As part of revising Annex 15, the definition of PQ has also changed. 68.2% answered question 5 (Do you understand the new PQ definition?) in the affirmative, for 1/5 (20.8%) the definition is not clear and 10.4% also answered no. This means that almost 1/3 of the participants are not sure about the new PQ definition. 

The answers to question 6 on how the participants assess the fact that a minimum of 3 validation batches can show the validation of a process were relatively evenly distributed. 39.6% would like further explanations. 37.5% will continue to "always" make 3 validation batches. 22.9% believe that the requirement may lead to confusion (see Figure 2).

 
Figure 2: Distribution of the answers on 3 validation batches

47.9% answered yes to question 7 (Do you understand what the revision means by hybrid approach for process validation?). 52.2% in total answered "not clear" or "no". 

More than half of the participants assessed removing the routine validation (question 8) as understandable as it is replaced by the ongoing process verification. But 36.6% would still like to regularly revalidate based on a risk assessment, and 6.4% even without a risk analysis. Just as many participants will only do this in a sterile area (e.g. at Medial Fills).

In relation to question 8, we asked question 9 to find out if the participants expect the ongoing process verification to involve additional work. 60.4% answered yes. For 1/4 the question was not clear and 14.6% do not believe it will generate additional work. We asked the 14.6% to give reasons for their assessment. In summary, it can be said this group considered this requirement already currently fulfilled (e.g. through APR, current monitoring).

The answers to question 10 were also interesting (Do you think that the requirements of packaging validation will require more work?). While 35.4% answered yes, it is (still) not clear to just as many (35.4%) and 29.2% answered no. We also asked those who answered yes to substantiate their answer. In summary, it can be said that the answers reveal that little (or less) was validated in this area in the past. 

69.4% answered question 11 "How do you handle the fact that only PDE is stated as the acceptance criterion for the cleaning validation (even for old products)?" with "not clear yet". 22.4% will start pharmacological investigations to obtain PDE calculation data. 8.2% want to keep the old limit values since they do not have data to calculate PDE values.

Question 12 relates to question 11 and also deals with the subject of cleaning validation (How will you deal with the fact that the number of validation batches for cleaning validation is no longer specified?)
69.4% answered that they will determine the number of cleaning validation runs based on a risk assessment. 16.3% will continue to do 3 runs and implementation is currently still unclear to 14.3%.

When asked question 13, to what extent does it conform with the FDA process validation guidance, 68.9% answered 75-100%. 30% answered 50-75%, 4.4% said < 50%, 6.7% answered 100% conformity.   

The answer to the last question (no. 14) on how the revision is generally assessed is very interesting:

The verdict is surprisingly positive (very good: 6%, good: 52%). 28% are satisfied. Only 14% would like improvements made and we specifically asked these people what improvements they would suggest. More precise information was requested and a greater comparison with the FDA process validation guidance, particularly with reference to the terms PQ and PPQ. One comment was even that the document raises more questions than it answers.

  
Figure 3: General assessment of the revision

Conclusion
The participants have an overall positive opinion of the revision of Annex 15. In total 58% consider the document to be very good or good. 28% said the revision is "satisfactory". Some of the new options are already being used by the industry (e.g. temporary release, combinations of qualification stages). Easing the requirement for FAT/SAT tests ("could") compared to the draft was well received. 68.8% find it good. The new PQ definition is now surprisingly clear (68.2%), on the other hand, almost 1/3 of the participants are still unsatisfied with the definition. Just as with the survey about the draft, there is still considerable uncertainty regarding the 3 validation batches. Here the industry would like more specific information or to carry on as previously ("always produce 3 batches"). The hybrid approach is also only clear to just under 50% of participants. With the request for ongoing process verification, the majority of the industry (60.4%) believes this will result in additional work, while 50% also believe discontinuing the routine revalidation will result in additional work. The analysis of the industry on packaging validation is also varied. Around 1/3 believe this will result in additional work, but almost as many think the opposite and also 1/3 cannot currently say whether any additional work will arise. The industry is mostly sceptical about the PDE concept in connection with the cleaning validation. For 69.4% the concept is not yet clear and just under 1/5 would like to start pharmacological investigations to calculate PDE values. The industry is dealing very pragmatically with the discontinuation of the three batches during cleaning validation. 69.4% would like to determine the runs based on a risk assessment. The majority of participants believe it conforms with the FDA process validation guidance to a relatively great extent.

Details of the survey will also be discussed at the ECA Annex 15 Conference, which will take place in Berlin, Germany, on 25/26 November 2015.