OPQ’S GRACE MCNALLY ON PROCESS VALIDATION AT FDA AND EU

At a Process Validation Interest Group session at the PDA/FDA conference, OPQ’s Grace McNally presented a detailed comparison of EU Annex 15 and FDA’s 2011 process validation guidance, and provided case studies illustrating process validation issues that FDA investigators are finding during inspections.

It has been some time since we first started working on FDA’s process validation guidance draft that came out in 2008. We were working on it for a couple of years before that. So it has been some time. Anyway, thank you. I am happy to be here this evening, and I appreciate that so many are staying for this late session.

When I was invited by PDA, the invitation was really geared at FDA’s perspective about Annex 15, which [Moderator Scott Bozzone from Pfizer] just said is going to be finalizing. I will spend some time speaking about that and how it compares and contrasts to the 2011 FDA guidance on process validation.

In doing that, I also have to mention the guideline on process validation for finished products from the EU, because those two documents, Annex 15 and the [‘Guideline on process validation for finished products – information and data to be provided in regulatory submissions’], really need to go hand-in-hand. I will talk about that some more.

And then I have a few case studies at the end of my talk – some examples of process validation issues that I saw from an inspection report or a 483. Maybe that will be fodder for starting an active discussion, which is really what I think these interest groups are supposed to be.

The 2011 FDA guidance for industry, ‘Process Validation: General Principles and Practices,’ is a GMP document. It does not address what is to be submitted in an NDA, ANDA, or BLA. It is focused on the GMP perspective. There are other policies and guidance that FDA uses to communicate expectations in terms of what should be submitted in an application. As you know, that may differ depending on the type of drug that you are working with. Our guidance applies to all drugs, and that would include, of course, our OTC monograph products for which there is no pre-market clearance.

Now I mention the EU. I use the term EU sort of loosely, as some of these come out under the auspices of the EC, the European Commission. But throughout my slides, you will just see EU, which means European Union. It may be under the EC or from the EMA.

Annex 15 is focused on GMP aspects, whereas this guideline on information to be provided as part of the regulatory submission also speaks very heavily about process validation, but it is talking about what goes in the dossier. Those two documents work together. So in drafting Annex 15, the working group members were very cognizant of what was in this process validation guideline for information to be

submitted. Previously, I believe those documents were called notes to guidance, and they changed the moniker of those documents.

Similarities

I will start off in the next few slides talking about what is the same. That is the focus. Because I think in general, despite some differences in these documents, the overarching message is the same: Quality risk management applies at all stages of the product lifecycle. That is true on both sides of the pond.

There is an expectation from both parties that science-based process development is taking place and that high level process understanding is being achieved, because that is going to be the basis for setting up your Stage 2 work – your initial demonstration at commercial scale that this commercial process will reliably produce drugs.

In FDA speak, we call that ‘Stage 2.’ In the FDA world we are using ‘process validation’ as an overarching umbrella term to capture the whole lifecycle, including design. Whereas in the EU nomenclature they acknowledge that there must be process design, they just do not wrap that under the ‘process validation’ term. So when they say ‘process validation,’ they are really speaking to that Stage 2 activity.

Both groups agree that it is a lifecycle approach – that a robust, controlled process reliably delivering consistent high quality drugs demands a persistent commitment to, and resources invested in, the scientific studies, the analyses, and the monitoring and maintenance of the process over the product lifecycle. That is a uniform theme in all of these documents.

FDA and our EU counterparts believe that and put out there very clearly that your validation exercises and work must be done before the product is commercialized. This is done as a reasonable protection to the consumer. There is some opportunity for concurrent release of lots that are in process validation studies, or Stage 2 studies, as FDA likes to refer to them. But it is not considered routine. We are clear in our document. FDA is clear that it would be rarely used.

It comes down to a risk assessment benefit to the patient, because there is a risk to a patient. There is a quality risk to the product and therefore a risk to the patient if you do not have your process validation, your Stage 1 and Stage 2 work, done and done well, in order to assure that there will be consistent quality in every unit and every lot and that the drug supply will be reliable. And our EU counterparts acknowledge that as well.

If you were just at the breakthrough therapies session, you know that there may be situations there where a concurrent release approach could be entertained. But in general it should be prospective.

As far as the number of batches, FDA and our EU counterparts believe that this needs to be justified. In Annex 15, and I think in the guideline for submissions, they retain this idea of a minimum of three batches. But that said, it also goes on to say that your decisions with regard to the study design should account for the normal expected range of variation or what that variability of your process is likely to be. So there is some idea conveyed in this that exploration of input variability and variability in the process has to be taken into account when deciding how you are going to execute your Stage 2 studies.

If you have read FDA’s guidance, the use of statistical tools and analyses is very heavily emphasized in the document. There are references to PAT [process analytical technology]. Certainly continuous manufacturing processes may employ PAT, and others as well. There are references to multivariate statistical process control and other statistical tools that will support conclusions about process stability and process capability. There are recommendations that data be statistically trended.

A common theme is state of control. Stage 3 in FDA’s guidance is referred to as ‘continued process verification.’ In the EU documents, Annex 15 in particular, have chosen the phrase ‘ongoing process verification.’

The reason they selected that is because they were trying to get away from this confusion that has resulted in the acronym CPV, because it is being used in two different ways: FDA’s guidance uses it in the Stage 3 realm, and it is ‘continued process verification.’ In ICH Q8 R2, it talks about ‘continuous process verification,’ and that is described as a different approach to process validation. But it is really more associated with the advanced technologies and continuous monitoring that some of the new sophisticated manufacturing methods employ.

In either case, that ongoing process verification, continued process verification, is the same idea. Data should be collected and trended. There should be verification of quality attributes controlled throughout, and the measurement of process stability and process capability.

There is this idea of change control that is the same in both documents. You need a plan. You need to plan for changes and anything that may impact the product quality or reproducibility. There is an expectation that any additional studies – be they design studies, requalification studies, or verification studies – will be undertaken.

Differences

There are some differences. In the EU document they talk about critical quality attributes and critical process parameters and that you must validate those. At the same time, that guideline, the one that talks to or speaks to what to include in your submission, does bring up and invoke this idea of non-critical – a summary of other non-critical attributes or parameters, which will be investigated or monitored during the validation activity.

Now on the FDA side, we do not make the distinction between critical and non-critical. The guideline makes an assertion that criticality is more of a continuum. Some things are more impactful relative to others. We expect that the manufacturers and the sponsors will do risk assessments and development studies that will establish these relative impacts and then put in place a control strategy that is commensurate with the risk – where it falls on that continuum. Your strategy for controlling it will be correlated to the degree of risk.

So, the number of batches question – as I mentioned earlier, the EU documents say you must justify them, but at a minimum three could potentially be considered a successful process validation. Right after saying that, they invoke other things like, ‘well, it will depend on complexity, previous experience, the depth and degree of your process understanding and your process knowledge.’ It is in there because I think other guidelines they have have always set that as a minimum. But I do not think their philosophy is any different from FDA, which is that you have to declare and be clear on what it is you are trying to prove. Then design the study to get the data that will answer the questions that you set out to answer.

FDA’s guidance is not specific. And that was deliberate on the part of the drafting group, because we wanted to focus the attention on the manufacturer’s responsibility to develop the criteria. And obviously the number of batches is one of the criteria that needs to be built into your study. But it is not the only criteria. It simply will say in the FDA guideline under the section about your PV protocol that you need to describe the data to be collected and when and how it will be evaluated. Built into that is the idea that you must select a number of batches.

What you are going to do with those batches? What sort of data are you going to collect from those batches? What sort of comparisons and analyses are you going to do between batch data? That is something that has to be put down in your protocol. How many lots? As far as FDA is concerned, nothing is written in stone. But it does have to written in your protocol.

Regarding statistics and variation: In the EU documents there are certainly a lot fewer references to statistics. It is very heavily emphasized in FDA’s. For example, some of the language in the FDA guidance will say, ‘to understand and detect variability in the process’ and ‘react to unintended and undesired variability.’ And we also make a statement that we recommend a statistician or somebody who is trained in these techniques to develop a data collection plan and the statistical methods to be used when gathering the data and then analyzing it.

Another difference I think that is important is that FDA makes a recommendation for the transition between Stage 2 and Stage 3 regarding the heightened sampling and monitoring. It is very specific about doing this for the purpose of gathering sufficient data to generate significant variability estimates. Because the FDA guideline is really driving home the point that variability is what is underpinning this whole operation. And understanding what is acceptable and what is not is really the job of the operations and process development and validation and tech ops teams.

The EU makes two references in Annex 15, and I am not sure how many are in the guideline, about what to submit in your dossier. But although they do not make as many heavy references to statistics, they are certainly expecting that they be used where appropriate.

Here are a couple of quotes about statistics. There are two messages in this. I will read the first one: ‘To call on the statistician after the experiment is done may be no more than asking him to perform a post-mortem examination. He may be able to say what the experiment died of.’ The point there is that you need to have your statistician or somebody who is trained in that field be involved in the team and the planning up front.

I think another quote gets to something that we see a lot, which has to do with, what is the question you are trying to answer? This quote says, ‘the statistician who supposes that his main contribution to the planning of an experiment will invoke statistical theory finds repeatedly that he makes his most valuable contribution simply by persuading the investigator to explain why he wishes to do the experiment.’

That resonates with me, because I think we frequently run into situations where the parties responsible for getting this process up and running and showing that it works have not clearly articulated what questions they are trying to answer. There is a plethora of ANSI standards and various statistical standards that can be applied. But you can only apply them when you know what question you are trying to answer, because they

answer different questions. That is something to keep in mind. Have these parties as part of your team early on and articulate what it is you are trying to prove.

Annex 15 addresses other various specific processes such as transportation, packaging, and cleaning validation, and it also speaks to a standard versus a non-standard process. The FDA guideline is not that detailed. The FDA guidance for industry is speaking about processes generally, but does not delve into the various types of processes that need validation.

It is important to know too that FDA’s guidance is general principles. So if you are working with a process for which there is a more specific guidance – aseptic processing is a good example, because there is a 2004 aseptic processing guidance – it is best to defer to the specific guidance as a primary and the 2011 principles as sort of a secondary guidance. Because it is general principles, we think it does apply, whether it is cleaning or water systems or packaging. There is nothing so specific that you could not carry it forward to a specific type of process.

Also, Annex 15 has a lot of details about things like site transfers and bracketing approaches – it talks about user requirements and user specifications. It invokes the design qualification, installation qualification, operational qualification, performance qualification, and when you might use those and when they can be combined.

It speaks to factory acceptance testing and site acceptance testing. And our guidance, the FDA guidance, does not get into that level of detail. Not because these issues would not be supported by FDA, it is just not intended to go down to that level of detail. That ends my comparison of Annex 15 and the FDA process validation guideline.

Case Studies

I will move now to some examples from some 483s and EIRs [establishment inspection reports] that I have looked at.

Mixing and Filling Operation

For this first example, there are maybe five or six slides on this, because there are a lot of aspects to it. Just to set it up, the background, this was a company that was validating a mixing and filling operation. This is the Stage 2 work, what [the EU] would call the process validation. They had elected to make four batches. Each batch consisted of a certain number of units with a certain number of grams for each unit. But the bulk of the batch size was going to vary.

They were also going to use an API from a different source for one of the batches. So they were deliberately introducing some variability, which is a good thing – something that should be considered. And I know that question kind of looms large often: Do I intentionally add input variability during my PPQ? What are the pros and cons of doing that?

I think there are a lot of pros in doing that. Certainly there is a risk, because the whole point is to show the robustness of the process. What is robustness? How well your process tolerates input variability and yet

has consistent output variability, be that an intermediate or the drug itself. But you could probably reap rewards by learning upfront very early that your input variability will have an effect.

Presumably if you have done a lot of comprehensive Stage 1, you already have some ideas about how much input variability your process can take before it begins to give you undesired output variability. Anyway, that is the setup.

One of the first criticisms or questions the investigative team had had to do with the sampling plan. So they had some in-process controls for a number of attributes. I believe there was a filling volume or a mass bulk, mass filling in-process control specification. And they were using this mil standard, general inspection level two.

One of the discussions with the company was, you are doing a process validation or Stage 2 study, and you selected – and this was a key attribute – general inspection level two, not the more conservative level one. You would ask yourself, wouldn’t you want to have a more focused, more tightened sampling during PPQ? That is a question.

The other issue that was raised with them was that their acceptance criteria listed the AQL as a limit of 0.1%. But when she looked at the samples and the acceptable defects, it turns out that that AQL was incorrect. So the parties driving this process validation effort were using a plan, selected an AQL, and it was not matching up with what they were actually sampling – the number of samples they were taking. They were not at all familiar with the operating characteristic curve for their sampling plan.

This seems pretty basic. If you are doing a Stage 2 study, you should have some understanding of what your sampling will provide you, what sort of conclusions you can make, and what sort of protection that sampling plan provides. And the operating characteristic curve is a key element of a sampling plan.

So the protocol stated something like, ‘the PPQ batches would be considered acceptable if all in-process control specifications were met.’ But they did not really speak in the protocol to the process. It was just that the batch would be okay. But there did not seem to be any discussion of how to make the conclusion about the process. This sort of inter-batch analysis focused on an intra-batch analysis. Even at that, I do not think it was particularly in-depth.

There were some out-of-specification results in the in-processing sampling, which in discussions with the company representatives, they attributed to some equipment target set-points that were intentionally set near upper and lower specifications, which is not good or bad. But there was not any description of this procedure or this intent during this protocol.

As a result, during the execution of this study they were making some adjustments. They told the inspection team that they were trying to see if they could bring this attribute back into the acceptable range. So there was some sort of experimentation going on during this PPQ study. You can debate whether that is a good thing to do or not. Again, it did not seem to be controlled. And that was the objection.

And it was not successful. They did not meet all of their criteria. Nevertheless, the report recommended going to reduced testing for all of their in-process testing following the testing of the PPQ batches. And the reason, when questioned, was ‘that is standard practice’

Is that standard practice reasonable or scientifically-based for reducing sampling and monitoring – particularly when your criteria were not met, you did not understand your sampling plan, your criteria were not particularly rigorous, and it is time to go to reduced testing? The whole thing was less than ideal.

In discussing this, they asked, ‘how do you justify your in-process sampling plan?’ Well, it helps to understand sampling plans, and certainly have people credentialed and on staff as part of the team who understand what they mean.

They talked about some other sampling plans that actually addressed how to make decisions in that regard – switching rules, when you might reduce testing, and what might justify reduced testing. These are examples. These are not requirements. These are not FDA requirements. These are just standards that are out there that can help inform decisions like this.

The ANSI/ASQ z1.4 would recommend that, in general, ten successful batches must be completed. And in the ISO 2059, the switching rules would require 15. The details of those plans would have to be reviewed and evaluated to see if they are appropriate. I am just putting them out here as examples of the sort of things that were discussed.

Extended Release Tablet

This example is an extended release tablet. It is not an unusual outcome. There were intermittent failures on stability. There was a dissolution problem at nine and 12 months. The basic criticism was not getting to root cause. There seemed to be indications that an excipient may be playing a role in this.

It was within specifications. Certainly, this is a story that has been told before here. The excipient can be very influential. The investigation just was not going to the depth and breadth that it needed to.

We do not know that this excipient was ultimately responsible for this dissolution problem. But the criticism: Often you will find process validation issues tied to investigations that never got far enough down to the level of granularity to target what needed to be addressed. This is one of those.

Purified Water System

This is an example of a purified water system where there just was not anything in place really. Operating ranges were not established. Comprehensive monitoring procedures were not established. So once we got out of Stage 2 where we were moving into routine production, what is the plan for monitoring?

That is something I have seen FDA investigators raising. And I am glad they are, even in the pre-approval realm where the validation does not need to be completed, if we are talking about small molecule products, in order to get an approval. But certainly as I mentioned earlier, it has be prospective. So before you make those

drugs available to patients and healthcare professionals, your company should have achieved a high degree of assurance in that process.

Once you move out of Stage 2 into Stage 3, what is the oversight going to look like? Is that proceduralized? Do you have plans and procedures in place? The EU talks in terms of protocols. On the FDA side we do not necessarily think in terms of Stage 3 as being under a study protocol. But certainly your routine SOPs should account for how you are going to monitor what data you are going to collect, when you are going to collect it, and how you are going to analyze it. What are your intentions in that regard?

Again, certain other key things that should be in place in a water system schedule and procedures for sanitization were not present. And a basic such as calibration of gauges was not in place. This was not a well thought-out validation of a water system.

Tablet Weight Checks

This is interesting example as it kind of gets to SPC [statistical process control]. This was a tablet. And they were doing in-process weight checks. They had set some alert and action limits.

And upon first blush, they sort of sounded statistical, because a lot of the procedures were using terminology such as ‘minimizing product variability,’ having ‘a control,’ ‘control process capability,’ and ‘maintain process control.’ But a further dive into the data and the procedures showed that there was no analysis of variability at all. The distribution of the data was not evaluated or identified or addressed in any way.

They were not utilizing variability to generate these alert and control limits. But they were sort of claiming in their procedures and paperwork these sort of capability statistics. It was kind of a house of cards. And once the team was pulling it apart, they realized that there was nothing behind it. It sounded good. But in order to make statements about capability, you have to be doing some sort of variability analysis. And they were not.

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