MONTHLY U OCTOBER 2015...of the number of batches used in the PPQ runs a state of control, referred...

MONTHLY UPDATE - OCTOBER 2015


GMP/INSPECTION

• Clarifying Questions Upfront is Key in Process Validation, US and EU PV Principles Align – CDER’s McNally .....4

UNITED STATES

UPDATES IN BRIEF - p. 32

US CMC: ● PDUFA Comments ● eCTDs ● Biotech Regulation ● ANDA LabelingUS GMP: ● Compounder Sterility ● CBER Untitled Letters ● Indian API Ban ● Syringe Labeling ● Bulk Drug Compounding ● Dispenser Product Training

EU CMC: ● EMA on Immunogenicity ● Scientific AdviceEU GMP: ● MHRA on GSK China Plant ● APIC on Particles ● Annex 16 ● Supply Chain Documentation

INTERNATIONAL CMC: ● Japan Orphan Drug Training ● Canada DMFs ● Russia/USP MOU ● China Review ReformsINTERNATIONAL GMP: ● Medicrime Convention ● MHRA /India MOU ● India GMP Penalties ● India Regulator Training ● Canada Bioanalytical Method Training ● Brazil Drug/Bio Guides ● Taiwan GDP Compliance ● WHO on HVAC ● Novartis India Plant

FDA WARNING LETTERS AND RECALLS POSTED IN OCTOBER - p. 39

EUROPE

GMP/INSPECTION

• PIC/S is Impacting Process Validation Expectations in Asia Pacific, Although They Vary in Practice, ISPE’s Asia Network is Reporting.........................................................................................................................................................................25

INTERNATIONAL

GMP/INSPECTION

• Risk Assessments, Data Integrity, Documentation, and Deviations Will be High on EU Radar Screen in Auditing Process Validation, with Revised GMP Annex 15 in Effect.......................................................................................................14

VOL.7, NO.6


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UNITED STATESClarifying Questions Upfront is Key in Process Validation, US and EU PV Principles in Alignment —CDER’s McNally FDA is advising industry to ensure that their process validation teams clearly articulate and document the questions they are seeking to answer up front, prior to collecting data or executing process qualification (PQ).

Beginning with the questions in mind and following up with supporting sampling plans and statistical tools will increase the chances for a successful and compliant PQ effort, agency officials are stressing.

In a presentation on the current FDA and EU expectations for process validation at a PV Interest Group session held at the PDA/FDA Joint Regulatory Conference in late September in Washington, DC, Office of Process and Facilities (OPF) Division of Inspectional Assessment Acting Branch Chief Grace McNally emphasized the importance of framing the PQ questions prior to creating or executing the plan.

OPF is part of the new Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ). McNally joined OPQ from CDER’s Office of Compliance, with the shift in its focus during the center reorganization (IPQ October 26, 2014).

McNally has been a leading policy maker for FDA in the process validation arena. She helped author FDA’s 2011 PV guidance and served as the agency representative on the drafting team for the revision of EU Annex 15, which became effective at the beginning of October (see story on pp. 13-23).

FDA’s basic PV philosophy, which lines up with that in Europe, she emphasized, is “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.”

The agency guidance is not specific – for instance, on the number of batches needed – “because we wanted to focus the attention on the manufacturer’s responsibility to develop the criteria,” she explained. Instead, the section on the PV protocol simply says “that you need to describe the data to be collected and when and how it will be evaluated.”

The protocol, she said, needs to address “what you are going to do with those batches, what sort of data are you going to collect from those batches, and what sort of comparisons and analyses are you going to do between batches.”

US and EU Are Aligned on Principles

In her presentation to the PDA interest group and during the extensive Q&A that followed, McNally expanded on the PQ design theme, discussed the similarities and differences between the FDA and EU guidance documents, and provided case studies illustrating process validation issues that FDA investigators are finding during inspections.

McNally began her comparison of the FDA and EU PV guides by noting that “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.” [Editor’s Note: McNally’s complete remarks are provided below.]

The EU rapporteur for Annex 15, MHRA inspector Norman Gray, speaking a week later at the ISPE/PQRI Process Validation Conference in Silver Spring, Maryland, similarly asserted that “the two documents are adopting a similar approach with small differences.”

McNally explained that there is an expectation from both parties that science-based process development is taking place and that high level process understanding is being achieved. She characterized that as “critical” to an initial demonstration at commercial scale that the commercial process will “reliably” produce drugs.

Both FDA and the EU regulators emphasize a “lifecycle” approach, which McNally maintains “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.

The regulators are also in agreement regarding the need for: ● completion of the PQ component of validation prior to product commercialization ● thorough risk assessments to ensure product quality and patient protection ● justification of the number of batches used in the PPQ runs ● a state of control, referred to by FDA as ‘continued process verification’ and by the EU as ‘ongoing process verification,’ and ● a strong change control system to plan for changes that may impact the product quality or reproducibility.

http://www.ipqpubs.com/news/cders-office-of-pharmaceutical-quality-will-become-functional-in-january-following-commissioners-call-for-commodity-oriented-centerfield-alignment/



Criticality Continuum, Statistics Stressed in US

While the “overarching messages” are the same, McNally did highlight some differences in emphasis or attention given to issues such as the concept of criticality and the use of statistics, and to specific details.

Annex 15 addresses critical quality attributes and critical process parameters and the need to validate them. FDA’s guidance, on the other hand, addresses criticality as a continuum – pointing to the need to establish relative impacts and put in place a control strategy that is commensurate with where the risk falls on the continuum.

Statistics is “heavily emphasized” in the FDA guidance, including the need to “to understand and detect variability in the process” and to “react to unintended and undesired variability,” McNally pointed out. Recommended is the engagement of a trained statistician to help develop the validation plan and use statistical methods to gather and evaluate the data.

While not focused on in Annex 15, the EU is “certainly

expecting that [statistics] be used where appropriate,” she commented.

MHRA’s Gray made the same point at the ISPE/PQRI meeting. While there is more emphasis on statistical tools in the FDA guideline, Gray confirmed that EU regulators do expect the data to be statistically trended and “would certainly promote the use” of statistical tools in validation activities.

Not in the FDA’s PV guideline, but discussed in the European document, are specific processes, such as transportation, packaging, and cleaning validation, as well as site transfers, bracketing approaches, and factory and site acceptance testing.

McNally noted that other more specific guidances from FDA, such as its aseptic process guideline, cover many of these topics and should be used in conjunction with the PV general principles guidance. She added that while FDA’s guidance targets general principles, these can be applied to specific processes such as cleaning, water systems, or packaging.

PFIZERS’S SCOTT BOZZONE ON THE INTERNATIONAL PV GUIDANCE LANDSCAPE

What I want to do before we start is give a quick overview of what is happening this year. This has been the most active year of process validation I have seen in my memory of reviewing these guidances.

There have been four guidances approved and effected this year. The first came out in March. That was Annex 15 from the European Commision. And that is becoming effective later this week on October 1st. That is on qualification and validation. I would say maybe about half of that is dealing with process validation.

A couple of days after that came out, the PIC/S adopted Annex 15 on qualification and validation. PIC/S is composed of 46 countries and 4 regulatory authorities [including] the US.

The third was in May, and that was from the China FDA, which was approved and is becoming effective in December. That is on qualification. That is called Annex 2. I believe the translation is qualification and verification. Still looking for the official English translation of that. We are probably going to do our own within Pfizer from China.

The fourth was from the WHO. That was again around May or June. That is on non-sterile process validation. The four of these quidances this year are very similar. Even though the WHO is on non-sterile process validation, it still has the three stages with the life-cycle and the continued process verification stage at the end.

In his opening remarks at the PDA Process Validation Interest Group session, Pfizer Senior Manager Scott Bozzone, who leads the IG, commented on the activity in the international PV guidance landscape in 2015.

Case Studies Explore PV Concerns

In the third section of her presentation, McNally provided four case studies demonstrating PV concerns investigators have found during manufacturing inspections.

The case studies involved: ● a mixing and filling operation

● an ER tablet ● a purified water system, and ● a tablet weight checking operation.

Concerns investigators found in the mixing and filling operation included the sampling plan, the measurement standard being used, and the study conclusions, among others.



In a Stage 2 study, McNally pointed out, “key elements” of the sampling plan are the operating characteristic (OC) curve – a plot of the probabilities of accepting a lot versus the fraction that fail – and selecting a correct acceptable quality level (AQL). In this case, the firm was “not at all familiar” with the OC curve, and had selected an incorrect AQL.

In addition, the mil standard being used was for inspection level two, rather than the “more conservative” level one, which would be more appropriate for a PQ study, McNally maintained.

Regarding the study conclusions, although the PQ was not successful – not all acceptance criteria were met – the resulting report recommended going to reduced testing. The reason, when the firm was questioned, was “that is standard practice.” McNally questioned whether that standard practice was “reasonable or scientifically-based…particularly when your criteria were not met, you did not understand your sampling plan, and your criteria were not particularly rigorous? And it is time to go to reduced testing? The whole thing was less than ideal.”

Queries Raised on Engineering Batches and Legacy Products

In the Q&A after McNally’s presentation to the PDA interest group, a participant asked if she thought that an engineering or technical batch could be released for sale provided that not many changes would be made for the PPQ batch.

Noting that she has been asked the question before, McNally responded, “I would say no.” She pointed out that the purpose for doing an engineering batch is to gain process knowledge or product understanding. “I do not think that you can switch the intent of the lot afterword. But there will always be exceptions.”

The discussion turned to validation of legacy products, with a participant noting that in many cases there is insufficient Stage 1 (process design) data. “Are there cases where you can use the ongoing commercial data and historically review that to define your operating ranges and call it validated?”

McNally replied that there is no need to recreate what happened in the past. “Start where you are,” she advised.

Noting that the FDA guidance allows the use of manufacturing data, she added that new, additional experiments may need to be performed to show the “current situation on the ground in the plant right now.” If the work is being done to support a change, “are there any variables that require some pre-study before implementing

the change? If so, you would need to do that.”

Another participant pointed out that when specifications for legacy products were originally set, his company did not understand the full range of process variability, resulting in the need to make process changes.

“You are obligated to make changes that need to be made,” McNally said. She pointed to a case study in an FDA training course regarding a 38-year-old NDA that was having intermittent failures and unexplained excursions. In the case study, the company maintains that the product and process were already approved, and it did not feel it needed to address the failures.

“The full range of variability that is going to present and what that is going to mean on the output, which we are trying to keep consistent, is not going to be fully known at the time of launch,” McNally noted. “This is why the emphasis on Stage 3 is important in the guidance.” She advised manufacturers to “keep your eye on the ball, which is variation coming in and variation going out, and what the right analyses are to measure and quantitate that and make statements about the variability.”

Continuous Manufacturing, Batch Numbers in Focus

Pfizer Pharmaceutical Sciences Technology Executive Director Phillip Nixon, who gave a presentation at a continuous manufacturing session earlier that day, asked McNally to comment on the differences between process qualifications for a continuous manufacturing process vs. a batch process.

Regarding a continuous manufacturing qualification, McNally commented that “I know there are a lot of questions about how to do statistical analysis with large sample sizes and lots of data points. I think the biggest differences are the software, the sensors, calibrating the sensors, and the models. That is a whole different approach.”

“You can do a lot in one single run,” Nixon interjected. “You can run for a long time and do a lot of different things.”

“That is right,” McNally replied. “That is why batch size is left open.” She also emphasized that the work the developers need to do to deploy the software and sensors “successfully, with confidence, and with demonstrated, documented confidence, is different than the batch manufacturers’.”

She also commented that the pharmaceutical industry as a whole would be “well-served if everybody moved to this higher level of manufacturing. You cannot require it. But that is what we would like to see happen.”



In response to a question regarding the appropriate number of batches to use for a process qualification exercise and what issues regarding batch size investigators are seeing in inspections, McNally returned to her theme regarding up front planning and how the data are collected and evaluated.

“I do not think we are seeing a lot of criticisms about the number of batches,” she said. “It is more like what I showed in the first case study. There is a bigger elephant in the room than the number of batches. Regardless of [how many batches], you need to understand what you are doing. The criticisms are around not understanding the sampling plan.”

The questions an investigator would ask, McNally said, are: “What are you doing with that data? Why are you collecting it? How are you collecting it? How frequently are you collecting it? How are you analyzing it? To answer what question? And are those the right questions to draw the right conclusions?”

Progress in Guidance Implementation Mixed

The discussion turned to the progress industry has made in implementing the principles in the FDA PV guidance and the barriers to its implementation.

Valsource Principal and Chief Operating Officer Hal Baseman, the current chairman of the PDA board, asked McNally what level of implementation she has seen during industry inspections.

She responded that while some firms “wait on the sidelines until a regulatory authority makes an issue of it during an inspection,” other companies have taken the initiative to implement the principles “because they know that it brings value to their company and patients. Reliable and consistent product has got to save tons of money over the long run, not to mention the supply chain – a reliable drug supply…. I would say it has improved. But there has not been a wholesale adoption.”

The OPQ official asked the audience members for their views on why some companies “resist” implementing the principles in FDA’s PV guidance.

One participant replied that, “at least for oral solid dosage forms,” data collection is an issue. “The data collection systems are just not there in our manufacturing areas. It requires that we put three months or six months worth of data on the table for someone to data mine. The systems are not integrated to an extent that we could have something elegant like the contact lens people do, where they are doing continuous manufacturing and continuous process

verification right on the line. The contact lenses get dumped if they do not meet spec.”

Another audience member commented that “data collection strategies in support of continued process verification and integrated IT systems can be used” to bring the data together and analyze it.

Baseman characterized the discussion as “hugely important” because of the number of new technologies and products being developed “that do not lend themselves to traditional manufacturing or traditional validation batch types of things. And what I hear is process validation as a possible barrier…. This should be an enhancement to process improvement and not an impediment.”

A third participant pointed to the financial pressures on the generics industry that disincent an extended commitment to the validation work.

“On the branded side you have years to develop process. On the generics side, the money is made in the first 180 days and the only thing that matters is ‘first to file.’ The way it is set up now, you do not have to even have three full scale batches to file. A lot of times you only have six or eight months to do the validation. Management wants to know how many batches. You plan it and put it in the schedule and you launch.”

When the validation batches are done, the participant continued, “there is no time to make a change. In three or four years my product is worth nothing and we are done. If the agency is really serious about requiring that work, you have to change the economic rules under which we work. If I get halfway through the validation and have to change a parameter, we have just lost our window. I am not going to make any money on the product. So there is no incentive to do all of this work. That is the playing field.”

“That is a big question,” McNally acknowledged, and “is above my pay grade.”

LINKS:

• FDA 2011 PV Guidance

• EU Annex 15

• EU Process Validation Submission Guideline

http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf

http://ec.europa.eu/health/files/eudralex/vol-4/2015-10_annex15.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162136.pdf



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

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.

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.



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.



Difference

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-specificatio 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 Systems

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 to 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.

Jerry

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EUROPERisk Assessments, Data Integrity, Documentation, and Deviations Will be High on EU Radar Screen in Auditing Process Validation, With Revised GMP Annex 15 In EffectRisk assessments, data integrity, documentation organization and deviation handling are issues that will be high on the radar screen of European inspectors in reviewing how companies are validating their processes, in accord with the increased emphasis the issues have received in the revision of EU GMP Annex 15.

Annex 15, which covers the qualification and validation of processes from a GMP vantage point, became effective at the beginning of October. The PIC/S GMPs match those in Europe, and PIC/S followed suit in adopting the annex revision in early October. [Editor’s Note: See story on pp. 24-30 for a review of the impact PIC/S is having on the process validation expectations in the Asia Pacific region.]

The EU last revised the annex in 2001. A concept paper explaining the motivations for the revision was released by EMA’s GMP/GDP Inspectors Working Group (IWG) for comment in late 2012 (IPQ February 12, 2013). Among them are technology advances, changes to the EU GMPs, the incorporation of ICH Q8-11 quality management principles in alignment with FDA’s PV guidance, and the rewrite of the PV drug product submission guidance.

A draft of the Annex 15 revision was issued for comment in February 2014. The final version, amended to reflect the comments, was issued in April 2015 – effective six months later.

The EU “Guideline on process validation for finished products – information and data to be provided in regulatory submissions” reached its final form in early 2014 and became effective the following August. [Editor’s Note: For an analysis of the final PV submission guideline and its relationship with the Annex 15 rewrite effort see IPQ March 27, 2014.]

Providing a timely review of the newly effective Annex 15 at the ISPE/PQRI meeting on process validation held at the beginning of October was its rapporteur, UK Medicines and Healthcare products Regulatory Agency (MHRA) Senior GMPD Inspector Norman Gray. In his presentation, Gray discussed: ● the revision process on the annex ● the changes made in the revision ● how it compares with FDA’s process validation guidance, and ● recent MHRA PV inspection findings.

Gray noted that there was significant comment on the annex revision draft, particularly among small to mid-size companies and consultants, with 44 organizations and individuals responding.

He singled out a response, in particular, from a consultant in cleaning validation as presenting “some great ideas. And we certainly took a lot of the things that he pointed out on board.”

Risk Assessment is a Lifecycle Process

Central to the revision process for Annex 15 – as it was for FDA in revising its PV guidance – was incorporating the concept of the validation lifecycle.

“We now expect that validation is not treated as just a one-off alternative for when you are transferring a product from development to the manufacturing site, or you are transferring an old product to another site,” Gray explained. “It is throughout the lifecycle of the product from initial development through to discontinuation of the product.”

Pivotal to the shift to a lifecycle PV approach is the incorporation into the revision of the “ongoing process verification” concept to define the post-marketing phase. Gray pointed out that the concept matches that of “continued process verification” in the FDA PV lexicon – with the altered terminology selected by EMA to avoid confusion with its use of the term “continuous process verification” as an alternative approach to process validation.

The lifecycle concept comes squarely to the fore in the risk assessment context.

Bringing the annex into line with the ICH guideline meant incorporating the expectation that risk assessments be done throughout the lifecycle of the product, Gray commented. The EU views assessing the risk to the product, to the validation, and to ongoing supply as important in increasing “the chances of success for the validation.”

The importance of risk assessment is highlighted in the opening section of the annex, but the words are not repeated through the document, the rapporteur explained, as “we did not want to end up with a document that mentions risk assessment on every line.” However, “it is implicit in all of the document.”

http://www.ipqpubs.com/news/ema-guidelines-on-process-validation-filings-for-biotech-substances-and-drug-product-advancing-along-with-gmp-annex-15-revision/

http://www.ipqpubs.com/news/ich-q8-11-oriented-submission-and-gmp-expectations-for-process-validation-and-other-quality-issues-taking-shape-in-europe/

http://www.ipqpubs.com/news/ich-q8-11-oriented-submission-and-gmp-expectations-for-process-validation-and-other-quality-issues-taking-shape-in-europe/



Saying that risk assessments are required throughout the lifecycle “implies that they are dynamic and they are going to change over a period of time,” Gray clarified. “Therefor is it is important that companies outline their approach to risk assessment and how they are going to update these at any time.” He suggested that “the most appropriate place for that could be in your validation master plan. But alternatively, it could be somewhere else.”

A participant at the session directed attention to the evaluation of risk in the context of ongoing process verification. He noted that his company was looking at the risk associated with the product and using a three month review cycle where the risk warranted doing so, and then amending that over time, while defaulting to the annual review where the risks were low.

Gray commented that the key lay in the company performing the risk assessment.

“If you have a new product where you have lack of information, lack of knowledge, you need to do it more frequently. Similarly, on the other end of the spectrum, if you have got work done on a product where you are not seeing any issues, the [performance qualification] is clean, you get no complaints, no deviations…there may be potential justification to extend that out. But again, you have to justify that.”

While the EU treats risk assessments “seriously,” a lot of companies fall down in their execution, Gray stressed. “They can be quite poor at identifying the risks.”

In the inspections findings component of his presentation, the MHRA inspector commented again on inadequate risk assessment processes. “A lot of companies just copy it from one product line to another product,” he said, “without looking at the specific attributes of the product and the manufacturing.”

Validation Includes Drilling Down on Data Integrity

Gray explained how EU and FDA inspection experience in recent years and the changing environment led to addressing data integrity in Annex 15.

Noting the importance of having data that is complete and accurate, Gray stressed that firms will be expected to “do some checks in data integrity when you are preparing and reviewing validation documents” – and not just spot checking for typing errors, but “drilling down into the data” and confirming that it is accurate in validation reports.

At overseas sites, the MHRA inspector said, “you want

to ask them for the log books to confirm that the product validation batches were actually manufactured at the time they said they were manufactured. You might want to look at sample receipt logs to confirm that the validation samples were actually received in the laboratory. You may actually want to drill down and look at some chromatograms to confirm that the results were as expected in the validation report. You may want to look at the audit trails.”

Development Data Needs to be Findable

As part of the knowledge management responsibilities, the revision emphasizes the need to have the PV-related documentation readily available and in a searchable form.

“We have made it a requirement that any data that is available for product development should be available at the commercial site,” Gray explained. “That does not mean it has to be physically present at the site, but they should have access to it. We do not expect a siloed R&D to put up their defensive walls and not allow production to access that sort of information, because it is important to insure a continuity of supply and quick resolution if things start to go wrong with products.”

Also emphasized in the revision is the role of deviations in validation as an early warning mechanism, and the need for their proper investigation.

In discussing recent PV-related inspection concerns, the MHRA official noted the finding of deviations that have been simply stored away in validation reports and not further addressed. These deviations should go into the formal deviation handling system, he cautioned, “so at least if you find a problem with a product and you do your search of historical deviations for that particular product, you are likely to find it, which may help you solve the problem.”

Other of the more specific changes in the revised annex, as delineated and contextualized by the annex revision rapporteur in his talk, include: ● tightening up on the use of concurrent validation ● clarification of the linkage with the EMA PV submission guideline – for example, regarding non-standard products, and ● removal of retrospective validation as an option.

Annex 15 is included in Part 1 of the EU GMPs covering finished products. Gray noted that some of the updates are not reflected in the coverage of process validation in Annex II for APIs, which has not gone through a similar revision process as of yet.



He also expressed some concern that more had not been done in the current revision to “reduce the documentation burden to companies” – and the burden to inspectors facing the “soul dropping” task of reviewing a trolley with “fifty folders of process validation work.”

Referencing the “long list” of PV-related deviations Gray provided in his presentation, an attendee asked whether any stuck out as particular problem areas.

The MHRA inspector responded that it really depended on the company, and that there were not any prevalent, systemic issues. He added that the database the EU keeps on inspection deficiencies shows relatively few for process validation vs. other areas.

While Not Emphasized, Stats Are Important, Gray Notes

Among differences in Annex 15 from FDAs PV guidance is less emphasis on statistical techniques. However, Gray noted, “we certainly promote the use of them in validation activities.”

During the Q&A, he was asked to comment on the motivation for not making the value of using statistical tools more explicit in the annex.

The EU GMP is focused on general principles, and “we are trying not to be too specific in what we say because different companies will have different resources. So we try to create a lot of flexibility when we are writing a new guidance.” Companies already have “a lot of things to address with the changes to Annex 15,” and the process in the EU tends to be evolutionary rather than revolutionary, he said.

However, the rapporteur recognized that the revision could and “perhaps should have emphasized [statistics] a bit more” and suggested that the issue may be sorted out in the next revision.

MHRA’S NORMAN GRAY ON ANNEX 15 REVISION AND PV INSPECTION

At the ISPE/PQRI Process Validation Conference in Silver Spring, MD in early October, MHRA Senior GMP Inspector Norman Gray discussed: ● the revision process on Annex 15 ● the changes made in the revision ● how it compares with FDA’s process validation guidance, and ● recent MHRA PV inspection findings. Gray was rapporteur on the Annex 15 revision.

I was the rapporteur for Annex 15. It sounds like a grand title. But basically it means that I am the project lead. So I end up doing most of the work and all of the others make comments on the work. It can be a difficult role sometimes.

This presentation is in four parts. The first part is about development of the revision of Annex 15. The second part explains the main changes of the document from the previous version. The third part is doing a comparison between the EU guidance and the FDA guidance. And the fourth part is giving you some examples of where some companies do not do validation particularly well.

Annex 15 Development

I would just like to start off by telling you a little bit about the history, the timing, and the consultation process for Annex 15. In the EU, there is a defined process for developing a document. Notice that Annex 15 is the main guidance document for validation.

The first version was published way back in 2001. So it has been 14 years approximately since we got around to doing the revision. The revision is out of inspectors’ control – it is through the planning group at the European

Medicines Agency. They decide when a document is going to be changed. One thing I did notice when I was researching this presentation is that it took us 14 years to revise the document. And I think it was a similar time frame or a lightly longer time frame when the FDA revised its document in 2011. So it maybe a document that people do not want to touch too much. I think it opens up too many worms.

LINKS: • EU Annex 15 • EU Process Validation Submission Guideline

http://ec.europa.eu/health/files/eudralex/vol-4/2015-10_annex15.pdf




I have explained the role of the rapporteur. It also involved inspectors from other European member states. We had some people from Ireland, Germany, Italy, and Portugal. We also had some representatives from the European Medicines Agency. And for the first time in the revision of an EU guidance, we also had a representative from PIC/S and also from the FDA. The aim is to try to make sure there is a more global harmonization of regulatory documents. We found it very useful.

And in this presentation, I would like to formally acknowledge the support of Grace McNally, who was the FDA member on the drafting team. Because of that, we would hope that there are a lot of similarities between what we use in the EU for compliance and what you use in the USA for compliance.

So let’s move on now to look at some of the timing. If you do a quick calculation from the first date to the last date, we were working on this project for about two-and-a-half years. So we started off in August 2012 when the drafting group was first established.

The first public consultation was on the concept paper. And that started in November 2012. Now, I will just briefly discuss what a concept paper is. Basically, a concept paper is the plan and the main changes to the document. So it is why we are changing the document and how we are going to go about changing it. In essence, we wanted to really bring it up to date to make sure it really reflected ICH guidance and all sorts of things like that. That date was November 2012.

We then went through the process of preparing the Annex 15 draft, which would then go out for public consultation. And it did in fact go out for public consultation in February 2014.

It was then adopted by the European Commission after they had a quick look over it to make sure there were no significant implications to Europe. And then it came into force in April 2015.

There was a plan to publish it on the first of April 2015, but we did manage to convince them otherwise, because we did not want to publish on what we call April Fools’ Day, which is when there are things that come out that are not true. So we published it on the second of April.

There is usually a six-month period to allow companies to look over the guidance and to implement it into their systems on site. As you are aware, it is now eight days since it came into force.

I am pleased to say that I did my first inspection of a US company this week, and they had done their gap analysis to see what the differences were between the EU guidance and their current procedures. I was most impressed. Usually we find that it is a couple of months after the implementation date that they actually do something, or they do not actually know the implementation date and they have not done anything at all. So that was good. That cheered me up a little bit.

So let’s talk about the consultation process. We do have a consultation process. We try not to impose guidance on our stakeholders. We do try to give them an opportunity to contribute.

And in this instance there were effectively two consultations. We had the consultation on the concept paper. And there were approximately ten to fifteen companies, groups, etc. that replied. And they were generally positive about it. Again, it is a broad document, so you do not really expect many significant issues at that point in time. We are only looking to see if we actually missed something really significant.

The second consultation is more important. That is when the first draft is actually visible by stakeholders. And we usually allow about a three-month period for people to look over it.

In this particular instance we got a good response. We had forty-four organizations responding. These organizations could be an individual. A lot of consultants seemed to respond. So maybe there was not any work on the weekends and they decided they wanted to do something, so they responded. It gives them something different to do.



You also find that you get some pharmaceutical companies responding. Interesting to note that it is mainly the smaller and middle level companies that respond. We did not get many responses from very large pharmaceutical companies. You can speculate on the reasons for that. I will leave it up to your imaginations to work that one out.

The best response I actually saw was from a consultant who did cleaning evaluation. There were some great ideas. And we certainly took a lot of the things that he pointed out on board. I do not know if he is in the audience here, but thank you very much. It was most appreciated.

So as you can see, we generated a lot of paper, similar to a normal validation study. We generated 131 pages of comments for review. We are obliged to go through every single response that we get. And if we accept it, we mark that we have accepted it. And if we do not accept it, we have to give an explanation. And somebody actually does look at these to make sure that we avoid prejudices – that issues like that do not interfere with taking on board good ideas. I just want to reinforce that if you do make a contribution, we do take it into account. And we thank you for all of the contributions that you make.

There are also other sorts of review processes – for example, the other EU inspectorates. There are 56 members of European community. They will also make comments on the draft. So that was the consultation. You can see from the number of organizations and the volume of work it provided that it was quite successful.

Changes to Annex 15

So now I want to move on to talk a little bit about the main changes to Annex 15. So this is the second part of the presentation. What I have done is broken it down to the main sections of the document and left out all of the stuff about equipment qualification.

General Changes

In all EU guidances there is usually a ‘principles’ section that really just summarizes the rest of the chapter. In this instance, we decided that there was so much in the principle section that we had to split some of that into another general section. So there are actually two sections in this document as opposed to just the principle section.

It may seem hard to believe that the concept of a validation lifecycle was not mentioned in the original draft in 2001. So obviously we had to create that. We now expect that validation is not treated as just a one-off alternative for when you are transferring a product from development to the manufacturing site, or you are transferring an old product to another site. It is throughout the lifecycle of the product from initial development through to discontinuation of the product.

To make sure that the Annex complied with all the ICH guidance, there was an expectation that you include risk assessments throughout the lifecycle of the product. And again, we consider risk assessments as important because you can then assess the risk to the product, the risk to the validation exercise, the risk to the ongoing supply of the product, and therefore it increases the chances of success for the validation. So in the EU we do treat risk assessments seriously or importantly. However, in execution I think that a lot of companies fall down in terms of risk assessments. And I think the key factor in which they fall down is the identification of the risks. They can be quite poor at identifying these.

You may find that other than in the principal and the general sections you do not see the words ‘risk assessment’ used much throughout the rest of the document. And the reason for that was we did not want to end up with a document that mentions risk assessment on every line.

So the approach was to put it into the general section and the principle section and then it was implicit throughout the rest of the document. We did not want to burden people with that many words. So just because it is not mentioned further down does not mean that you should not be doing it. It is implicit in all of the document.

Obviously process validation exercises and all of the validation in general can be quite complex, so therefore it is important that the validation is organized appropriately.



We would expect when you are doing validation that you use personnel who are suitably trained in validation activities. It is a complex task. You are looking for people who have the technical knowledge, attention to detail, follow procedures appropriately, and who can see small things happening that have not been taken into account initially, but may have a significant impact later on in the process. So they may be able to identify something that later becomes a problem. You are looking for validation to be performed by people who know what they are doing.

It is also important that there is appropriate quality oversight of validation. We are quite relaxed in the EU as to where validation fits into the organization. Personally, I am not too concerned if it reports to the quality department, or if it reports to production, or if it reports to another technical part of the organization. However, it is important that there is that quality oversight. If you decide that you get that more by having a validation department that ties to the quality department, then so be it. But there are other options.

Again, we have made the comment in this section that use of risk assessments are required throughout the lifecycle. That implies that they are dynamic and they are going to change over a period of time. Therefore it is important that companies outline their approach to risk assessments and how they are going to update these at any time. And perhaps the most appropriate place for that could be in your validation master plan. But alternatively it could be somewhere else.

You are probably all aware of data integrity. Data integrity is a hot topic within the regulator environments. I have been to places in India where there has been poor data integrity. And as a result, these companies have got into problems. I have accompanied some of your FDA inspectors in India, and data integrity issues have been identified.

It is important that data is complete and accurate. We would expect you to do some checks in data integrity when you are preparing and reviewing validation documents. It is not just checking that there are no typing errors in the document. It is looking more broadly at the data. It is drilling down into the data.

If you do an overseas site, for example, you want to ask them for the log books to confirm that the product validation batches were actually manufactured at the time they said they were manufactured. You might want to look at sample receipt logs to confirm that the validation samples were actually received at the laboratory.

You may actually want to drill down and look at some chromatograms to confirm that the results were as expected in the validation report. You may want to look at the audit trails.

We have an expectation that you do not just accept the data in the report – that you confirm the data in the report – because the environment in which you operate has changed. I think in the past, we as regulators had a general expectation that companies would do the best thing for the patient. However, experiences in recent years have made us change that. We are a bit more skeptical than what we have been in the past. And that is why data integrity has been added into Annex 15.

Documentation is an important part of validation. And unfortunately in the revision of the document we probably have not managed to reduce the documentation burden to companies. Personally I wish we had, because there is nothing that sort of makes my soul drop as when you are inspecting the rear end of a trolley that has fifty folders of process validation work. And you think to yourself, ‘it is going to take me two days to go through that, and it was only a three day inspection.’ And unfortunately, I do apologize that we did not manage to reduce the amount of documentation that we need to generate.

However, what we have emphasized is the fact that you need to obtain information. You need to make sure that the information you have, that the documentation that you have, is readily available and in a form that allows you to search. So if during the validation lifecycle you run into a problem, you have the information available that allows you to understand the process, if part of the process is unclear, and therefore have a better chance of being able to solve the problem.

Again, Annex 15 emphasizes the role of deviations in validation. We would hope that we would not have any deviations. But obviously there will be deviations, and you have to treat them properly. You have to investigate them. Because



sometimes a deviation in a validation stage is really an early warning of some issue that may potentially happen in the future. Deviations may be an early warning mechanism for you. So it is important that they are investigated promptly.

I sometimes feel that validation – you write a protocol, you write a report – can become very mechanistic. So if you have acceptance criteria, at the end of the report you say it met all of the acceptance criteria. However, I think we are looking for more than that. There is a risk that becomes too mechanistic.

We are looking for a conclusion, the views of the person who did the validation, and any suggestions that he had during the validation. We are looking for not just to make sure it met the acceptance criteria, but actually looking at the data to see if there are abnormalities, such as one set the data at one end of the range and the other set of data is at the another end of the range. So we are looking for not just doing the work, but critically evaluating the data and making sure it is appropriate.

We do mention in Annex 15 the use of statistical techniques. Perhaps the emphasis on the EU is not so much on the statistical techniques, but there is nothing to stop companies from using them. And we would certainly promote the use of them in validation activities.

Specific Change

The next part is to look at some of the specific changes to process validation in a bit more detail.

The first thing I would just point out to you is that you should not just look at Annex 15 as a stand-alone document. It is linked to another European document, and that document is called, ‘Guideline on process validation for finished products – information and data to be provided in regulatory submissions.’

Annex 15 ties in with that document. That is the primary document that somebody would use to make your regulatory submission. Annex 15 is how we confirm that the manufacturer is meeting the requirements for GMP and validation activities. So the two are linked.

And there is one specific section in that document that you may want to look at, where it defines two subsets of products. The first set is a standard product, and the other set is a nonstandard product. And a nonstandard product is defined as something that may have been novel, that may have new technology involved in it, or it may be an unusual dosage form.

For example, metered dose inhalers are included as a nonstandard product. Also products that are manufactured aseptically are defined as nonstandard, as well as products that are sterilized by a non-compendial method. They are defined as nonstandard. And the implications for that are that you have to do full scale validation batches for nonstandard products. So again, I do not have time to go into that document in too much detail, but it is a sister document and therefore essential reading if you are reading Annex 15.

You can see here we have sort of tightened up on the use of concurrent validation. We believe that it should only be used in exceptional circumstances. And that is similar to the FDA approach, where it specifically mentions shortages.

We have a statement that there must be a strong risk/benefit to the patient. You might find that difficult to understand. But basically what we are saying is there must be a benefit to the patient for you to do a concurrent validation. There should be no benefit to the company in terms of reducing inventory, increasing time to market, etc. It is all to help the patient. So shortages potentially could be a reason for using concurrent validation.

We put in the statement that it must be visible in the VMP [validation master plan]. You might ask yourself the question: Why in the VMP rather than the protocol? The reason for that is if you are inspecting a company that has fifty products, you are not going to look through fifty protocols. You do not have the time to look through fifty protocols. So we were looking for a quick way by which we can confirm how the company is operating.

If they send in the VMP, it is a cumulative list. It is for one year and then you update that list as you go along. And we



have a better chance of seeing it and therefore we have a better chance of being able to ask the company why they did concurrent validation. So it is purely from a selfish regulator inspector viewpoint that it was put in the validation master plan.

Again, in the 2001 Annex 15, we did allow retrospective validation. Now the view here is that prospective has prevailed. You have had fourteen years to move to the position of doing prospective validation. Therefore you have reached your expiration date. So we would expect that you no longer do retrospective validation. And again, that is very similar to what we see in the USA.

I have one word of caution for you. And that word of caution is that the scope of Annex 15 is finished products. And it is in Part I of the EU GMP guide. There is also a Part II of the EU GMP guide, which covers APIs. And it has its own section on validation. It now allows retrospective validation and also allows concurrent validation. Under certain circumstances they are justified. You need to be aware of this.

There is a statement in the principle that says that Annex 15 could be used for APIs, but it is not mandatory to use it for APIs. So we have that disconnect. And it is unfortunate that we are contradicting each other to a certain extent. But that is the way it works. All of these revisions are done independently of each other. And it just so happens that the API guide was being revised about the same time as Annex 15, and no one told us that that was the case or that they were not changing it to comply with what we had put in Annex 15. So that is an anomaly. Perhaps in the future it may be clarified.

We want to make it clear that Annex 15 applies to all dosage forms, new products, changes in products, and also to site transfers.

As I indicated, the submission document and process validation allows both a traditional and a continuous verification approach to process validation. It was interesting that in the consultation there was one comment from one individual that said that we should not allow the traditional approach to process validation at all because we should be trying to move the pharmaceutical industry to a more high-tech position. So his view was we should not allow traditional validation to improve the way in which we develop products.

However, we must remember that any guidance that we produce has to cover a wide range of companies. So it is big pharma, small pharma, generics companies, so therefore it is not something that we can force on them. Otherwise there would be no supply of products.

As regulators, we do try to reduce the workload to stakeholders. So we do allow you to take a bracketing approach. You also see we are matricing there. We had great difficulty in finding a definition for matricing. There is a lot of it in analytical documentation, but not so much of it in process validation. So you might see it mentioned there. But I think in the final version it is removed.

Some of your polling concerned legacy products. It has always been the requirement in Europe that if you have a marketing authorization for a product you are under a general obligation to keep that dossier up to date with current practices. So if you have a finished product specification that involves TLC with limited detectability, we would expectyou to update that to a UV HPLC method. So there is that general requirement has always been there for all products to keep them up to date.

However, in practice, you will find that a lot of companies do not do that. You will find a lot of products in Europe that are very old. They have not been updated for many years. So this was put in not to force, but to stimulate companies to recognize that and then to start to look at their older products, especially if they are transferring it from one site to another. And not just transferring it as it stands, but making sure that it is in a fit state to be transferred. So that is why we specifically make that statement.

Again, in the polling there was some discussion on the importance of CPPs and CQAs. We think it is important because it allows people to understand what the key parameters are for products when they are manufacturing them.



This ties in with ICH requirements.

We talked about briefly about validation personnel and their experience. We also try and emphasize the transfer of knowledge that translates to production personnel. In a lot of companies, it will be the R&D people or a specific

group that transfers products. However, you have to recognize that it is the production department that is going to have to make these products going forward. So the chances of success of the validation and the commercialization of the product is enhanced by involving the production personnel at the earliest stages. We have emphasized that in the document.

Tying in with knowledge management we have also made it a requirement that any data that is available for product development should be available at the commercial site. That does not mean it has to be physically present at the site, but they should have access to it. We do not expect a silo R&D to put up their defensive walls and not allow production to access that sort of information, because it is important to insure a continuity of supply and quick resolution if things start to go wrong with products.

We made a specific requirement that you cannot just make a validation batch and then decide to release it. You have to allocate that batch in advance to be released. In terms of the approach, we just expanded a bit more on the traditional approach. We have done this for many years. We made a series of batches and confirmed reproducibility.

The number three: We have had lots of debates about this. Do we just go and say that the company should make a number of process validation batches based on QRM principles? We considered that we could do that, but we did not want a lot of companies to not be familiar with what we were expecting. They were comfortable with the number three. So we decided, to avoid too much confusion because it was a significant change, to leave three as it is.

But basically we are giving them a warning we would expect it to be based on other criteria. This is a transition we want them to make. So in this version we still have three. The next reversion will not say three. It will be based on risk management principles. So we are really trying to make them evolve.

But as general guidance, if there is more variability in process validation results, or if there are any uncertainties, or the process is complex, we would expect the number of validation batches to increase.

As indicated, there is a continuous verificatio approach allowed now in the EU GMP. I am sure you have talked about it a lot in earlier presentations, so you probably know more about the subject than me. So I will not dwell very long on this slide.

There is also a hybrid approach. So as you have gained a lot of knowledge about a product over many years that is manufactured at the same site using the same equipment for a long time, then potentially you could move to a continuous process verification approach. Ongoing process verificatio is something new that has been introduced to EU GMP. Traditionally in the past, companies would maybe repeat the process validation based on a time interval. Five years was common. Some might repeat the whole process validation. Some might do an assessment. So they may look at the data and then decide if the need to do a process validation or not. So there were lots of approaches previously.

Now we are saying that it needs to be done for all products. So our definition: There is a monitoring process to confirm that state of control is maintained throughout that product lifecycle. The aim is to detect unplanned departures or unintended process variability from the process as designed. And I am sure that definition is not significantly different from how you use it in the USA.

How would we expect that to work in practice? In practice, companies spend an awful lot of time on what we call product quality reviews [PQRs] in Europe, and in America you call them annual product reviews [APRs]. We spend an awful lot of time preparing that document. And I have always thought, ‘do we actually get any benefit from doing it?’ So hopefully with the introduction of ongoing process verification, that could be used to confirm that the process is in a state of control.



There may also be some circumstances where you have a written PQR or you want to look at a specific issue. And under these circumstances you could also write a specific protocol or write a specific report to confirm some aspects of ongoing process verification. Again, the frequency by which you perform it should be based on the lifecycle. For example, if it is a new product, you would expect it to be more frequent than an established product.

I should have said at the beginning when I presented this that we changed ‘continued process verification’ to ‘ongoing process verification,’ because we thought there was confusion between continuous and continued. So the terminology has changed. I apologize for not saying that earlier. In American terms, this is continued process verification.

Some of the slides showed what we would expect from some of the older products. So if it were a legacy product you are manufacturing, we would expect ongoing process verification.

Comparing EU and US Guidance

The next section is just a quick comparison between the EU guidance and the FDA guidance. As I have indicated, there was an FDA member in the drafting group. She was quite vocal in ensuring that we took FDA requirements into account.

I just quickly tried to put together a slide that shows some of the criteria and how the FDA and EU guidance meets it:

● We have already talked about the scope of the document. The FDA document includes API. Again, this is the wording in the EU guidance – it is supplementary optional guidance for APIs, because they have their own section on process validation.

● They both have the lifecycle approach.

● They both emphasize that process understanding and knowledge is important. In terms of legacy products, I think FDA has looked to continually improve the process.

● As I have discussed, in the EU GMP, the process should be kept up to date with the current standards that we have.

● Good facility design and equipment qualification are prerequisites for process validation. That is recognized in both documents.

● Increased level of scrutiny, testing, and sampling during PV is recognized in both documents.

● The importance of documentation for validation is recognized. We require a protocol, a report, deviations, and clear conclusions.

● Data should be statistically trended. Probably in the US there is more emphasis on statistical tools in validation. We have only mentioned it once in the EU guideline. That is not to say that you do not need to include it. I think it is important personally that you do include it. And if you want to show state of control, then you must use some form of statistical tools.

● FDA references ASTM E2500. We would not endorse another document other than another EU document.

● Concurrent release is rarely used. Again, you want that to be defined in the protocol. For practical reasons as I have described, we would want that described in the validation master plan.

● Retrospective process validation: Again, both documents in the EU should be used.

● Processes should remain in a state of control during manufacturing.

● Again, FDA uses the terminology continued process verification, and we use the terminology ongoing process verification.



So hopefully these two slides will perhaps give you some confidence and some clarity that the two documents are adopting a similar approach with small differences.

Inspection Findings

The next stage of the presentation is to really highlight some of the things I or my colleagues have seen during inspections where companies could improve validation processes.

I am not going to go through them all. I am just going to highlight some of them. I am not going to spend much time on it because it is important that you are able to ask questions.

The section on organization and planning: It is important that there are good document links when you are doing validation. A lot of companies are not particularly good at that. I would expect some sort of pathway to show how all the documents link together. Because if you do not do it systematically, there is a good chance you will forget something and leave something out.

Using trend charts rather than control charts to monitor the process: A trend chart does not tell you about all that much. It just tells you what the value is. If you are wanting to control the process, then you need to use a control chart.

Some companies prepare a process validation protocol and then change that halfway through. It could be not a good thing to do, because you are keeping the existing results and making sure that they fit in without having to do any further work. It is especially important if you do some experimental batches up front to make sure that your protocols are achievable. We always encourage companies not to go straight into process validation, but to do the work upfront to confirm that it is going to be successful.

A lot of companies, especially in India, tend to get confused between process qualification of equipment and process validation, especially when introducing a new line at the same time that they are introducing a new product. It tends to get a bit messy there.

We have talked a little bit about data integrity. As an inspector, if you start to see discrepancies in reports, your eyebrows start to raise and you start to get questions in your mind about whether the data is correct and if it has been executed properly. It is important to make sure that everything is satisfactory.

I talked a little bit earlier about the process of developing risk assessments. The process can be very poor. A lot of companies just copy it from one product line to another product without looking at the specific attributes of the product and the manufacturing.

We still see some protocols that do not do any additional sampling. They just take normal one hour checks. They do a normal production and use that data.

And then another important point is that sometimes deviations are just stored in the validation reports. I think it is important in terms of understanding what has happened to the process to use the information you have to solve problems in the future. Deviations should not be treated as just validation deviations – they should go into the formal deviation system. So at least if you find a problem with the product and you do your search of historical deviations for that particular product then you are likely to find it, which may help you solve the problem.

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INTERNATIONALPIC/S is Impacting Process Validation Expectations in Asia Pacific Region, Although They Vary in Practice, ISPE’s Asia Network is ReportingThe strong influence of PIC/S in the Asia Pacific region is impacting the expectations for process validation, although those expectations vary significantly in practice, the ISPE Asia network is reporting.

Process validation has been an active area of both benchmarking and training in the ISPE Asia network, which includes 14 affiliates. Valuable insights have been gained on the progress to date in the PV arena and the gaps that would need to be filled to bring countries into full alignment with the revised PIC/S GMP Annex 15.

The PIC/S GMPs match those in Europe, and the Annex 15 revision was adopted by PIC/S in early October a few days after its effective date in the EU.

An analysis of how process validation is being handled across the Asia Pacific region was provided by industry consultant Maurice Parlane at the ISPE/PQRI PV meeting held in Silver Spring, Maryland in early October. Parlane is an active member of ISPE’s Australasia Affiliate, Asia Pacific Regulatory and Compliance Committee (RCC) and PQLI Process Validation Committee, and his talk reflected the sharing and benchmarking that has been taking place across the ISPE network.

The presentation on Asia at the ISPE/PQRI conference followed a review of the revised Annex 15 and its relationship with FDA’s PV guidance by the rapporteur for the annex revision, MHRA Senior GMP Inspector Norman Gray (see story on pp. 15-25).

Parlane discussed the impact PIC/S is having in Asia and how the relationship is playing out in individual countries and blocks across the region in the process validation context (see Parlane’s complete remarks on pp. 27-32).

“Probably the most significant trend in the AP region is the influence of PIC/S,” the industry consultant explained. “There are 23 countries in the region, and 18 are in some way influenced by PIC/S.”

The influence varies whether the countries are PIC/S members, expressing interest in joining PIC/S, or just using the PIC/S annex as a reference.

Even among PIC/S members, there is a lot of variation in which PIC/S guidances and annexes each chooses to adopt.

“If you are approved by PIC/S, it does not also mean that you have to use the whole code,” Parlane pointed out. He noted that while New Zealand and Australia have adopted Annex 15, “other countries can adopt various annexes as they see fit.”

Although PIC/S members need to prove GMP equivalence under PIC/S of their GMP system as a whole, “that does not mean that every element of the system needs to be there.” For example, regarding the PIC/S GMPs, some countries, such as the US, Canada, and Japan follow their own GMPs, and European PIC/S members follow the EU GMP guide.

Issues and Challenges Explored

Parlane laid out the PV issues and challenges in the AP region and how they are being addressed by both PIC/S members and non-members.

He highlighted an issue with the regulatory systems in the People’s Republic of China [PRC] and India that will be problematic from a PIC/S standpoint – a split in where responsibility lies for policy development and compliance enforcement.

The policy initiatives such as GMPs in those countries comes out of a “federal-type of system,” but the regulatory compliance is driven at a provincial level, the ISPE AP expert explained. “That is causing those jurisdictions some real issues in terms of compliance with PIC/S because…it is really about consistency in inspections.”

Parlane commented that the PRC, which has expressed an interest in joining PIC/S, is “probably more advanced in this area” than India.

Some countries in the AP region – such as Japan, Australia, and New Zealand – are “relatively mature in terms of GMPs, “probably due to the influence of affiliates of multinational companies that supply into the US or Europe,” he explained. Others face a variety of challenges.

The challenges include: ● language and culture, including accuracy of translations ● risk assessment, and how it is interpreted ● the value proposition of exporting products vs. focusing on the domestic market ● maturity of the industry and the regulatory agencies ● affordability of and access to training, and ● the ability to keep pace with



changing regulatory expectations.

“Imagine that your GMP system is still picking up risk and annual product review and computer system validation,” the industry consultant commented. “And all of these things are happening in the last two or three years. And now Annex 15 is in there as well. So really there is a lot of work for a lot of companies and for regulators in keeping pace.”

He noted that while ISPE is seeing “a lot of interest” from industry and regulators in keeping pace, the question remains whether that desire will translate into implementation. “I think there is still a big question around that. It is still going to take a while yet.”

ISPE Active in China Regulator PV Training

On the training front, the ISPE China affiliate has two ISPE-accredited instructors and has been running “a lot” of training courses in the region.

Parlane commented that it appears that the China FDA (CFDA) is “on a pretty steep learning curve.” He recounted attending an ISPE-sponsored PV training session for regulators at a conference earlier in 2015. “There was a lot of interest. There were 39 regulators there.”

However, the training of CFDA regulators and/or the influence of PIC/S may be bearing fruit in the PV area. A recently-released annex to its GMPs on PV, according to Parlane’s colleagues on the ISPE RCC, appears to be “well-aligned” with PIC/S. However, as an official translation is not yet available, Parlane commented that he “would not want to be the first one” to submit the information in a CFDA application.

During the Q&A after his presentation, Parlane was asked about China’s three batch requirement for process qualification, and what scale those batches needed to be.

The industry consultant said that he believed for finished product the requirement is three batches at full scale. Noting that his focus and expertise are more in the GMP area than the CMC area, he commented that “I do know from colleagues on the RCC committee that it is quite problematic and that there are some quite prescriptive requirements about registration batches in China…. It is quite complicated because the regulatory submission process is managed almost secretly from the GMP.”

ASEAN Making Progress

One group within the AP region that has made significant progress in terms of validation is the Association of South East Asian Nations (ASEAN).

In 2012, ASEAN published a guideline on “submission of manufacturing process validation for drug registration,” which allows for a quality-by-design (QbD) or a traditional approach. “They were well ahead of their time in terms of the rest of the region,” Parlane commented.

There is also a mutual recognition agreement between the ASEAN GMP inspectorates that was launched in 2009, where each member is required to have a PIC/S-equivalent GMP program. “Looking at PV,” he pointed out, “that means you would be thinking about lifecycle validation.”

CONSULTANT MAURICE PARLANE ON PV TRENDS IN THE ASIA PACIFIC

I am going to talk briefly about what is happening with process validation in the Asia Pacific [AP] region. The reason I am possibly qualified to speak about it comes out of the last three years being involved with the AP ISPE affiliate councils. In the AP region there are 14 ISPE affiliates scattered around. As you can probably imagine, process validation has been quite a hot topic for us…. We do talk about it a lot within ISPE. My presentation collates information from all of those sources.

GMPs

In talking about process validation, you cannot do that without discussing GMPs. So I am going to discuss GMPs quickly.

At the ISPE/PQRI PV meeting held in Silver Spring, Maryland in early October, industry consultant Maurice Parlane presented an analysis of how process validation is being handled across the Asia Pacific region. Borrowing on intelligence gathering and sharing across the ISPE Asia network, he provided background on what GMPs are being used in the region, and delved into the similarities, differences, and challenges on a country-by-country basis.



Probably everybody is aware of the PIC/S Annex 15, which is identical to the current EU Annex 15. In fact, they were both adopted at the same time. The implementation of that around the region has a lot to do with PIC/S.

Probably the most significant trend in the AP region is the influence of PIC/S. Just to highlight, there are 23 countries in the region, and 18 are in some way influenced by PIC/S.

This slide probably illustrates it in a little bit more detail (see box below).

The regulatory authorities within the region that are formal members of PIC/S are listed in this table. There are also a number of countries that are currently going through the PIC/S application process. Then there are regulatory authorities of countries that are expressing interest. And there are some that are not expressing interest but are still using the PIC/S guide. That relates directly or indirectly as you will see to Annex 15.

I have highlighted a couple here that are of interest to US companies. One is the People’s Republic of China [PRC]. Actually, the situation there and in India are quite similar in that the policy for GMPs in those countries comes out of a federal-type of system, but the regulatory compliance is driven at a provincial level. That is causing those jurisdictions some real issues in terms of compliance with PIC/S because, for those of you who are aware, it is really about consistency in inspections.

The PRC is probably more advanced in this area. They recognize this. They are talking to PIC/S. But India – and this is my opinion – basically recognizes the inability of the current system. But it does not appear they will be meeting with PIC/S anytime soon.

Just to illustrate a catch in the PIC/S assumptions and in particular the Annex 15 assumptions: Just because you are a member of PIC/S or are working toward membership does not mean that you are using Annex 15 or even the PIC/S GMPs.

What I have illustrated in a table here is how that can play out (see box below). In the left-hand column you can see that there are some jurisdictions around the world that use the PIC/S GMPs including, or maybe not including, Annex 15. There are also countries that use the EU GMPs. But there are also regulatory authorities that have their own GMP guide and are members of PIC/S – an obvious example being the FDA. So being in PIC/S does not mean essentially that you use Annex 15.

Also, if you are approved by PIC/S it does not also mean that you have to use the whole code. My country, for instance, New Zealand and Australia, uses Annex 15. Other countries can adopt various annexes as they see fit. While you have to prove GMP equivalence under PIC/S of your GMP system as a whole, that does not mean that every element of the system needs to be there.



Process Validation

I will move on now to some more validation related things. If you look across the region, there are markets – for example, Japan, Australia and New Zealand – which are relatively mature in terms of GMPs. That is probably due to the influence of affiliates of multinational companies that supply into the US or Europe. So those markets have a good understanding and are a reasonable way up in terms of GMPs.

Then you have areas such as Singapore and China, which are the tigers, I guess we call them, of the AP region, where there is a lot of investment and the rate of change is very great. They are becoming more popular locations. Those jurisdictions are developing quite fast.

Then we have the ASEAN [Association of South East Asian Nations] block, which I will talk about in a minute. They are mainly focused on manufacturing for themselves, although there is a certain element of export. There are some unusual things happening with process validation and GMPs in those regions.

I am going to specifically address China and India because of the regional jurisdiction of GMPs that I touched on, but also in those areas there are some challenges around GMPs and process validation. First of all, they still use their own codes and probably will intend to right through the PIC/S process. If they do, and there are some differences in their codes to match their local requirements, those things mainly relate to gaps or differences in interpretations.

One thing I would say, looking at the AP region in terms of GMPs and process validation in particular, there are some challenges. One of the most significant ones is the language and the culture…. Even with the intent to stay consistent, translations sometimes do not bear that out.

Process validation is premised upon risk assessment. It is a big jump to assume that Southeast Asian nations will have the same premise of risk around their operations that we would think of.

The other thing that is a bit of a challenge is the value proposition. We see this in China and India, in particular, and in other jurisdictions. Fundamentally, the governments in those regions are thinking about drugs for their people, not for Europe or the US. They are not necessarily invested in the value proposition of export. And some of those GMP requirements may not step up entirely to the mark. In fact, it is viewed as an impediment. Every country and every regulator is really concerned about their own people probably first and foremost.

Finally, and probably the most obvious one, is the maturity of the industry in those areas, and the regulators, to some extent. One thing I do notice is that the regional regulators, like the regulators in Southeast Asia, are very keen to learn. So at conferences like these it is not unusual to see a large number of regulators in the region. And they partake pretty actively in things like ISPE initiatives, which is really good.



ASEAN

I will just mention briefly the ASEAN region, because it is significant in terms of process validation. The countries are listed up here. ASEAN is an economic block, as you are probably aware. In 2013 they did some work around medicines and registration. A document called, ‘the submission of manufacturing process validation for drug registration’ was published in 2012, which is quite a while ago in PV terms. Interestingly, that document allows for a quality-by-design [QbD] or a traditional approach. They were well ahead of their time in terms of the rest of the region.

There is also a mutual recognition agreement between the ASEAN GMP inspectorates that was launched in 2009, where each member is required to have a PIC/S-equivalent GMP program. Looking at PV – that means you would be thinking about lifecycle validation. I have talked a little bit about some of the exclusions in there. But at this point in time, the uptake is pretty slow.

Singapore, Malaysia, and Indonesia have obtained PIC/S approval, as you saw in the previous slide. There is still a ways to go for some of the other regulators in the region.

To come back to PV specifically – it is complicated. I would say that the uptake is slow overall. I have mentioned some of the reasons why. When you look around the region, there are two tiers of understanding: There are those companies that are exposed either by being an affiliate or supplying a market where they are picking it up quite quickly. They are probably influenced by those connections. But by and large, the rest of the region is moving at its own pace. And that pace can vary significantly. And there are some challenges around that.

I mentioned the language and the culture. But one of the more significant ones we have seen is simply affordabilit . The ability to get your people out and learn about training is limited by either their own budget or their company’s training and development budget. It is also quite costly to get experts into the region.

China is a bit of a shining star in the ISPE circle right now. But if you look within the AP region, it is actually way up to the left of that region. And it is actually quite expensive to get there. You do not see a lot of ASEAN countries heading up to China for training, even though the training does seem to be in China. I think there is still a ways to go. There has been a bit of work in Singapore, but really the travelling distance is a bit of a journey.

My personal opinion is that many of the manufacturers in the region are going to struggle. It is not just the journey distance and the cost thing, but there is also the pace of change. In the US and Europe, we are used to GMPs that have been largely similar for a number of years. Process validation is a new thing into the GMPs.

Imagine that your GMP system is still picking up risk and annual product review and computer system validation. And all of these things are happening in the last two or three years. And now Annex 15 is in there as well. So really there is a lot of work for a lot of companies and for regulators in keeping pace. I think what we are seeing at the moment is a lot of interest. But will that hit the ground in terms of implementation? I think there is still a big question around that. It is still going to take a while yet.

I have some slides that I think you will be interested in around the current situation in Japan, China, the areas that I work in mostly, and India.

Japan

In terms of PV in Japan, the registration pathway can either be traditional of enhanced. Many of you may know that. The MHLW [Ministry of Health, Labor, and Welfare] will accept ICH eCTDs [electronic common technical documents]. Just in July they announced that they have fully adopted Annex 15 into their GMPs. Japanese pharma companies are pretty much on the ball from the look of it from all reports in terms of introducing lifecycle validation. That is what you would expect – that market is quite mature.

The ISPE Japan affiliate ran a process validation workshop a couple of months ago. It was very well-attended by industry. I think that is a market that you can say is not far behind what is happening here and in Europe. They are fully compatible. And they probably understand fully what is going on.



China

In terms of China, it is interesting. Many of you have been aware that China has published an annex to its GMPs,which is purportedly not dissimilar to what the US FDA process validation guidance is like. There are some interesting things in the translation. That is my opinion, because there is no official English translation at this point. What we have is a draft version of the document, which was published earlier this year and commented on quite widely. The final version was just published recently. It comes into effect on December 1.

As I said, there is no official English version. But from what I have seen and heard from colleagues in China is that it is well-aligned. But there are a couple of little hooks. For instance, registration in China still requires three batches. That is a regulatory requirement rather than a PV requirement.

There are a couple of other things it would appear, at least from the translation of the wording, that CPV is required to be managed in the protocol and a report rather than a plan going forward. I wonder if that is just a translation thing. But there has been a reasonable amount of discussion around how CPV might be managed. I think there are still some things to learn yet about China.

In China, the ISPE affilia has run some training. They have two ISPE-accredited instructors. There has been a lot of training run in that region. I would say that the CFDA is on a pretty steep learning curve. I attended a conference earlier in the year there and they had a preliminary session before the conference with the regulators, where ISPE presented some training on PV. There was a lot of interest. There were 39 regulators there.

I think it is fair to say that at least outwardly they look compatible, but I would not want to be the first one. That is based on comments I have heard from colleagues on the [ISPE] RCC [regulatory and compliance committee] who have been involved in CMC submissions. They say that outwardly it appears to be quite compatible as well. But when you submit, it is maybe not. I think there is more to come.

Singapore, Australia, and New Zealand

In terms of PV in Singapore, Australia, and New Zealand, we mutually recognize each other, which is handy. As I said before, the industry in these areas is reasonably well-influenced from international sources. We all use the PIC/S GMPs. However, none of us have actually adopted Annex 15.

This is one of the quirks I mentioned before about PIC/S membership – that you can actually be a PIC/S member and be current, but not necessarily have all of the annexes. We are currently using the old version of Annex 15. The GMPs we are using is actually four versions old. The situation is the same in Singapore and Australia.

I would say that from my experience CQAs [critical quality attributes] and CPPs [critical process parameters] have been in common use for quite a while. I think there was a bit of a move to update that around the time when the ICH documents were being talked about. It is not unusual to see that sort of terminology in documents and risk assessments. There has been a lot of training around it. But we are pretty much in a similar position to you guys. We are willing to learn. But there is quite an influence from multinational companies in terms of what is happening.

In these areas, there have been very few registrations or inspections completed that would have involved enhanced validation approaches. But there is a high degree of technical awareness, I would say. So generally speaking we are compatible, but because of the market size we are probably just not getting exercised, if that makes sense.

India

Regarding PV in India, some of you may be aware that the registration in India is managed centrally out of an organization. The GMP requirements are also managed centrally. They are quite different. They are modeled after the WHO GMPs. But they are not the current WHO GMPs. And they are not exactly the WHO GMPs. And they are not exactly the PIC/S either. I have given you a reference to where they are.

As far as ISPE is aware, there is no current plan for lifecycle validation in that region. And as I mentioned before, there is the problem of regional differentiation, or a system of GMPs.



I would say from personal experience that some companies are exposed to it. I have personally been to a company that has been doing work in this area. From what I saw at that particular company, their technical capability was very good. Their science was very good. But their story was not very well-presented. It did not link back to the development.

But the industry does appear to be aware. At least the responsible companies, if you want to call them that, are aware. ISPE is planning a whole conference on PV early next year. The industry, at least the larger companies and the affiliates, are actively training.

In that area, the regulations do not support lifecycle validation. I think it is a bit of a pick and mix as to whether it is good or not good.

Rest of the Region

In the rest of the region – and I have a list of the countries here – generally speaking, registration is still traditional. There is a lot of influence from the local requirements. I would suggest that anecdotally. It might be like a CTD, but there are other things that are required to be submitted. I think that PV could be viewed the same way. These countries are probably more inwardly focused perhaps than on export. So it is likely that PV in these regions might not be the full package, or they might have slightly different requirements.

There are various stages of maturity. And the GMPs are broadly equivalent to PIC/S. However, it is unlikely, at least in my opinion, that they will adopt Annex 15 for quite some time. And that is due to what I mentioned before. Literally, why would you bring another lot of hurt into your life?

There is quite a lot of work going on. There is a lot of interest, as I said. But the reality is that the focus of these countries is probably inwardly. So this would need to fit with their priorities.

The industry from what we can see in the region is actively training. As I said, it is really the export-only guys that will be thinking about Annex 15. That is a snapshot of the region.

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Updates in Brief

CMC/REVIEW

PDUFA Comment Period Extended

In the wake of a July 15 public meeting on the reauthorization of the Prescription Drug User Fee Act (PDUFA) for FY 2018-2022, during which FDA received a wide range of comments covering a variety of topics, the agency announced in the Federal Register that the comment process has been reopened and will extend until April 29, 2016. The original end date for comments had been August 15, by which time 70 sets of comments had been received. FDA said in the announcement that it was reopening the comment period to “allow interested persons additional time to submit comments.” Included in the comments at the July meeting and submitted to the PDUFA and GDUFA docket was a request from the International Pharmaceutical Excipients Council (IPEC) urging the agency to create a regulatory pathway for new excipients (IPQ August 29, 2015). eCTD Guidance

FDA announced in the Oct. 6 Federal Register the availability of a draft “eCTD Technical Conformance Guide,” a technical specifications document that provides specifications, recommendations, and general considerations on how to submit electronic Common Technical Document (eCTD)-based electronic submissions to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). In addition to an introduction and background section, the 19-page draft includes sections on general considerations, organization of the eCTD, issues and solutions, and references. The “issues and solutions’ section tackles: ● combining multiple 3.2.S or 3.2.P sections with similar metadata ● clinical study reports submitted in the incorrect section ● not applicable (N/A) or unassigned folders in Module 4 or 5, and ● multiple similar STF structures displaying in Module 4 or 5. Comments are due by November 20.

Biotech Regulation Framework Public Meeting

FDA announced an upcoming public meeting on “Clarifying Current Roles and Responsibilities Described in the Coordinated Framework for the Regulation of Biotechnology and Developing a Long-Term Strategy for the Regulation of the Products of Biotechnology.” The meeting will be jointly hosted by FDA on October 30 at its White Oak campus in conjunction with the National Science and Technology Council, the Office of Science and Technology Policy (OSTP), the Environmental Protection Agency (EPA), and the US Department of Agriculture (USDA). The meeting will be the first in a series designed to clarify: ● which biotechnology product areas are within the authority and responsibility of each agency ● the roles that each agency plays for different product areas, particularly for those product areas that fall within the responsibility of multiple agencies, and how those roles relate to each other in the course of a regulatory assessment ● a standard mechanism for communication and, as appropriate, coordination among agencies, while they perform their respective regulatory functions, and for identifying agency designees responsible for this coordination function, and ● the mechanism and timeline for regularly reviewing, and updating as appropriate, how to minimize delays, support innovation, protect health and the environment, and promote the public trust in the regulatory systems for biotechnology products.

ANDA Labeling Guidance

FDA has released a final guidance on “Acceptability of Draft Labeling to Support ANDA Approval.” The guidance allows generic drug applications to be approved on the basis of draft labeling rather than requiring submission of final printed labeling (FPL) as was previously the case. The approvals will occur so long as any deficiencies in the draft labeling are of an editorial or minor nature and the labels meet other agreed-upon recommendations. FDA notes in the three-page guidance that it is being implemented “without prior public comment” because the agency determined that the changes “present a less burdensome policy that is consistent with the public health.”

UNITED STATES

https://www.federalregister.gov/articles/2015/05/13/2015-11537/prescription-drug-user-fee-act-public-meeting-request-for-comments

https://www.federalregister.gov/articles/2015/05/13/2015-11537/prescription-drug-user-fee-act-public-meeting-request-for-comments

http://www.regulations.gov/#!docketBrowser;rpp=25;po=0;dct=PS;D=FDA-2010-N-0128

http://www.ipqpubs.com/news/relationship-with-excipient-providers-drawing-increasing-pharma-attention-bms-exec-stresses-ipec-urges-regulatory-pathway-for-new-excipients-in-gdufapdufa-comments

https://www.federalregister.gov/articles/2015/10/06/2015-25353/electronic-common-technical-document-technical-conformance-guide-availability

http://www.ipqpubs.com/wp-content/uploads/2015/10/eCTD_TECHNICAL_CONFORMANCE_GUIDE.pdf

https://www.federalregister.gov/articles/2015/10/16/2015-26311/clarifying-current-roles-and-responsibilities-described-in-the-coordinated-framework-for-the

http://www.fda.gov/NewsEvents/MeetingsConferencesWorkshops/ucm463783.htm

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM465628.pdf



GMP/INSPECTION

Compounder Sterility Issues

In early October, FDA warned health care professionals not to use drugs purported to be sterile that were manufactured by Park Compounding Pharmacy located in Westlake Village, California. The announcement came on the heels of an August 31 to September 11 FDA inspection of the facility that resulted in a six-page, ten-observation Form 483 that calls into question the sterility of the products produced. FDA investigators reported “insanitary conditions, including poor sterile production practices” and maintained that the firm lacked procedures to prevent microbial contamination of sterile drugs and monitoring systems to detect contamination in aseptic areas. In addition, the firm was cited for a “general room” in which materials were sterilized, that was also used as a break room where employees ate. In its announcement, FDA said that Park agreed to cease sterile manufacturing operations, but “refused” to recall products that had already been distributed. In mid-October, FDA warned health care professionals not to use products purported to be sterile from Qualgen in Edmond, Oklahoma, where a recent inspection found “insanitary conditions, including poor sterile production practices, which raise concerns about Qualgen’s ability to assure the sterility of drug products that it produced.” While Qualgen agreed to recall some of its products on the market, it said it will disregard FDA’s request to “cease sterile compounding operations until appropriate corrective actions have been implemented by the facility.” [For IPQ’s coverage of issues with pharmacy sterile compounding operations, click here.]

Bulk Drug Substances Compounding Guidance

In late October, FDA announced the availability of a draft guidance “Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act.” Section 503B was added as part of the Drug Quality and Security Act of 2013 (DQSA) (IPQ December 28, 2013). It describes the conditions that must be satisfied for human drug products compounded by an outsourcing facility to be exempt from certain FD&C Act requirements, including that the outsourcing facility does not compound drug products using a bulk drug substance unless it appears on an approved list established by FDA. The October guidance describes the conditions under which FDA does not intend to take action against an outsourcing facility for compounding a drug product from a bulk drug substance that does not appear on a list, as the list has not been finalized. In a separate announcement on the same day, the agency put forth a request for nominations for the list, emphasizing that the active ingredients submitted must not be covered under a USP/NF monograph or be a component of an FDA-approved drug. The agency had previously solicited nominations for the list, but some of the nominated substances were not supported by sufficient information for FDA to evaluate them. [For IPQ’s coverage of the guidance, issues, and regulatory actions in the pharmacy compounding arena, click here.]

CBER Untitled Letters

The Center for Biologics Research and Evaluation (CBER) has posted six untitled letters sent to companies making licensed allergen mixtures, maintaining that the failure to use “correct and consistent nomenclature” on their websites amounted to “inaccurate identification of the proportions of non-standardized extracts used to make licensed allergen mixtures,” which “can lead to mistakes in the diagnosis and inappropriate treatment of allergies.” The letters from Mary Malarkey, director of CBER’s Office of Compliance, were sent to Oklahoma-based Allergy Laboratories, Washington-based contract manufacturer Jubilant HollisterStier, Missouri-based Antigen Laboratories, North Carolina-based Greer Laboratories, California-based Allermed Laboratories and Texas-based ALK-Abello. The letters were identical with the exception of the appendices listing the firm’s mixtures and associated label concerns. CBER requests that the firms review the product nomenclature for all products provided in the letter and notify it regarding: ● the steps taken to properly identify the non-standardized allergenic extracts that are not identified, or properly identify the proportions of non-standardized extracts used to make licensed allergen mixtures, or both, ● proposed timeframes for submitting labeling supplements for product labeling that needs revision, and ● plans to update the establishment registration and product listing information including all currently manufactured products.

Indian API Import Ban

In mid-October, FDA placed an import ban on active pharmaceutical ingredient (API) manufacturer Megafine Pharma’s Nashik site in Maharashtra, India. The firm produces two dozen APIs for the US market, including for drugs intended to treat depression, multiple sclerosis, Alzheimer’s disease, and schizophrenia. FDA’s notice does not list the reason for the ban. The addition of Megafine to the import alert list makes a total of 47 Indian API and finished product manufacturers banned from

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm465582.htm

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/UCM465551.pdf

http://www.fda.gov/Drugs/DrugSafety/ucm466522.htm

http://www.ipqpubs.com/?s=%22sterile+compounding%22&submit.x=18&submit.y=5

https://www.federalregister.gov/articles/2015/10/27/2015-27268/interim-policy-on-compounding-using-bulk-drug-substances-under-section-503b-of-the-federal-food-drug

http://www.ipqpubs.com/wp-content/uploads/2015/10/Interim_Policy_on_Compounding_Using_Bulk_Drug_Substances_Under_Section_503B_of_the_Federal_Food_Drug_and_Cosmetic_Act_Draft_Guidance_for_Industry.pdf

http://www.ipqpubs.com/news/fda-moves-quickly-to-implement-compounding-provisions-of-drug-quality-and-security-act/

https://www.federalregister.gov/articles/2015/10/27/2015-27271/bulk-drug-substances-that-can-be-used-to-compound-drug-products-in-accordance-with-section-503a-of

http://www.regulations.gov/#!docketDetail;D=FDA-2015-N-3534

http://www.ipqpubs.com/?s=pharmacy+compounding&submit.x=0&submit.y=0

http://www.fda.gov/biologicsbloodvaccines/newsevents/whatsnewforbiologics/default.htm

http://www.accessdata.fda.gov/cms_ia/importalert_189.html?source=govdelivery&utm_medium=email&utm_source=govdelivery



exporting products to the US. According to RAPS Regulatory Focus, the firm was inspected in May and received a Form 483 citing issues with lab data manipulation, falsification, and a lack of investigations into lab discrepancies. [For IPQ’s coverage of data manipulation problems that FDA and other regulatory agencies have been finding in manufacturing inspections, predominately in India, click here.]

FDA Draft Syringe Labeling Guidance

FDA announced the availability of a draft guidance on “Selection of the Appropriate Package Type, Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use.” The guidance provides recommendations on the selection of appropriate package type terms and selection of appropriate discard statements for injectable medical products for human use, packaged in multiple-dose, single-dose, and single-patient-use containers. Specifically, it provides revised definitions for single-dose and multiple-dose containers, and introduces the definition of a new package type term, “single-patient-use” container. The guidance applies to New and Abbreviated New Drug Applications (NDAs and ANDAs), Biologics License Applications (BLAs), Premarket Approval Applications (PMAs), and 510(k) Premarket Notifications. The comment period extends until December 21.

Product Tracing Requirements for Dispensers

In late October, FDA revised its compliance policy guidance on product tracing requirements for dispensers under the Drug Supply Chain Security Act (DSCSA) to allow more time for firms to come into compliance prior to agency enforcement of the provisions. The original compliance date has been moved from November 1, 2015 to March 1, 2016. The original guidance, published in December 2014 (IPQ December 16, 2014), set July 1, 2015 as the compliance date, which was subsequently extended until November 1, 2015. [For IPQ extensive coverage on the DSCSA, click here.]

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http://www.raps.org/Regulatory-Focus/News/2015/10/15/23406/FDA-Bans-Imports-From-Major-Indian-API-Manufacturer/

http://www.ipqpubs.com/?s=%22data+integrity%22&submit.x=0&submit.y=0

https://www.federalregister.gov/articles/2015/10/22/2015-26849/selection-of-the-appropriate-package-type-terms-and-recommendations-for-labeling-injectable-medical

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM468228.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM453225.pdf?source=govdelivery&utm_medium=email&utm_source=govdelivery&

http://www.ipqpubs.com/wp-content/uploads/2015/01/DSCSA-Compliance.pdf

http://www.ipqpubs.com/gmp-policy/three-fda-guidances-on-drug-supply-chain-security-act-dscsa/

http://www.ipqpubs.com/?s=DSCSA&submit.x=0&submit.y=0

http://www.ispe.org/

http://www.usp.org/

http://www.biotechlogic.com/

http://www.parexel.com/

http://www.westpharma.com/

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CMC/REVIEW

EMA Immunogenicity Assessment Draft

On October 1, EMA released a draft guideline on “Immunogenicity assessment of biotechnology-derived therapeutic proteins” – a revision of its 2006 immunogenicity guideline. The executive summary notes that the guideline is being revised “on the basis of experience from marketing authorization applications and other new information.” The draft contains more specific require-ments for assays for immunogenicity, and includes a list of issues to be considered. Sections cover: ● factors that may influence the development of an immune response against a therapeutic protein ● potential clinical consequences of immunogenicity ● non-clinical assessment of immunogenicity and its consequences ● development of assays for detecting and measuring immune responses in humans ● immunogenicity and clinical development ● pharmacovigilance ● summary of the immunogenicity pro-gram, and ● an annex providing an example of a strategy for immunogenicity assessment. Comments are due by the end of January, 2016.

Scientific Advice Requests

In a press release published in early October, the European Medicines Agency (EMA) reported a “notable increase” in the first half of 2015 in marketing authorization applications for medicines containing a new active substance and for biosimilars. 77% of the applications in the first half of 2015 received scientific advice.” The agency asserts that the results demonstrate that EMA’s efforts to encourage applicants to seek interaction and dialogue with the agency “are paying off.” EMA maintains that the early dialogue accelerates approval timelines.

GMP/INSPECTIONMHRA Cites GSK Facility in China

In late October, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) issued a report of GMP non-compliance to a GlaxoSmithKline (GSK) plant in Tianjin, China, based on a June 2015 inspection. Inspectors cite a “critical deficiency” with regard to “system failures” that fail to ensure that the products manufactured meet GMPs and marketing authorization commitments. Specifically, the investigators noted: ● “Since 2005, the company identified tablet discoloration in the stability samples during the stability trials which did not meet the shelf life specification. No action was taken to assess the risk of the remaining products in the markets. Adverse trends in stability-indicating attributes were observed but not investigated.” ● “Failure to notify competent authorities on the discovery of defective products” ● “Failure to address the root cause dueto ineffective CAPA. Also a delay in CAPA implementation,” and ● “Failure to escalate the incident and conduct effective investigations in a timely manner.” The site manufactures the heartburn medicine Zantac for import into a number of European countries, including the UK.

APIC Guide on Insoluble Particles

The European-based Active Pharmaceutical Ingredients Committee (APIC) has released a “guidance” on “Handling of Insoluble Matter and Foreign Particles in APIs.” The 19-page document released by the industry association aims to “provide a basis for a common understanding regarding the presence of particles in APIs,” provide recommendations on how to minimize the risk of particles, how to test for them, and what to do when they are found. In addition to acknowledgements, introduction and purpose, background, and scope sections, it contains sections on: ● definitions of particles ● good practices to minimize the presence of particles in APIs ● analytical controls and acceptance criteria, and ● incident management. References and a glossary are also included.

EU Annex 16 Finalized

The European Commission has published the final version of the revised EU-GMP Guideline Annex 16 “Certification by a Qualified Person and Batch Release.” The annex covers QP release of medicinal products and investigational medicinal products (IMPs) for human or veterinary use for sale in or export from the EU. An important change from the draft made in response to stakeholder

EUROPE


http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/10/WC500195094.pdf

http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do?ctrl=searchGMPNCResultControlList&action=Drilldown&param=31740

http://www.gmp-compliance.org/guidemgr/files/20150626FOREIGNPARTICLEGUIDELINE_FINAL.PDF

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm



feedback is a provision allowing samples to be taken not only after arrival in the EU, but also “taken at the manufacturing site in the third country in accordance with a technically justified approach which is documented within the company’s quality system.” For samples taken outside the EU, the annex notes that they “should be shipped under equivalent transport conditions as the batch that they represent.” The annex is effective on April 15, 2015. [For a detailed history of the 2013 draft and the reasons for the revision, see IPQ August 4, 2013.]

Supply Chain Documentation

The EU has updated its GMP Q&A webpage to clarify the expectations for documenting and verifying the supply chain for active substances. The new entry calls for the supply chain for each active substance to be established and documented back to the manufacturer of the starting materials. It also calls for the supply chain risks to the documented. The EU further states that “control of each incoming consignment of active substance should include verification that it has been received from the approved supplier and approved manufacturer. The entire supply chain should be verified for a supplied batch periodically to establish a documented trail for the batch back to the manufacturer(s) of the active substance starting materials. The frequency of this verification should be based on risk.”

CMC/REVIEWJapan Orphan Drug Training

In its September newsletter, Japan’s Pharmaceutical and Medical Device Agency (PMDA) reported on a training session on orphan drugs conducted for its staff by European Medicines Agency Committee for Orphan Medicinal Products (COMP) member Segundo Mariz. The session, titled “Orphan Medicine Designation and development in Rare Diseases” outlined how the orphan drug designation is handled in Europe, including incentives and special measures EMA takes in reviewing applications after being designated as an orphan medicine. The participants “gained a further understanding of the support measures to promote research and development of orphan medicines and to accelerate getting their approvals,” the newsletter explains. Harmonization/convergence of orphan drug processes between Europe and Asian countries has been a topic of discussion at recent industry conferences (IPQ February 6, 2014).

Health Canada DMFs

In early October, Health Canada (HC) announced that, “effective immediately,” new Drug Master Files (DMFs) transactions related to existing DMFs (for example, letters of access, administrative information), and DMF updates must be provided in “non-eCTD electronic-only” format. By March 31, 2016, all existing DMFs in paper format must be replaced by a complete DMF conversion in “non-eCTD electronic-only” format. Failure to provide the complete electronic copy of the DMF will result in the DMF being suspended, the announcement notes. DMF holders and submitters can refer to a Health Canada guidance document finalized in September to assist them in the submission/conversion processes.

USP, Russia Sign MOU

USP and Russia’s drug regulatory agency, the Federal Service on Surveillance in Healthcare of the Russian Federation (Roszdravnadzor), signed a memorandum of understanding (MOU) in mid-October, extending an agreement signed in 2009, to cooperate on developing and implementing quality standards for drugs and their ingredients, RAPS Regulatory Focus reports. The agreement includes provisions aimed at harmonization of pharmacopeial requirements, promoting the use of modern laboratory standards, education and training programs on quality standards, and exchange of scientific staff.

China Reforming Drug Application and Review Process

China’s Standing Committee of the National People’s Congress (NPC), the country’s legislature, will hold a meeting from October 30 to November 4 to review proposals aimed at introducing a European-like market authorization holder (MAH) system and improve the China FDA’s (CFDA’s) drug application and review process, the Harvard Bill of Health Blog reports. It notes that pressure for the reforms is a perennial backlog of applications, estimated at over 20,000, due in part to a staff of 120 reviewers and an annual submission of about 8,000 applications. The primary tenets of the proposal focus on: ● providing CFDA more staff ● piloting an MAH system, and ● simplifying and improving the drug review and approval process.

INTERNATIONAL

http://www.ipqpubs.com/news/revision-of-eu-annex-16-clarifies-qp-responsibilities-in-an-increasingly-complex-supply-chain

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000027.jsp&mid=WC0b01ac05800296ca#section2

http://www.pmda.go.jp/files/000207596.pdf

http://www.ipqpubs.com/news/post-approval-change-regulatory-burden-draws-heat-at-japan-cmc-strategy-forum

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/notice_dmf_prep_fmm_avis_non_ectd-eng.php

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/ctd/gd_prep_non_ectd_ld-eng.pdf

http://www.raps.org/Regulatory-Focus/News/2015/10/21/23447/USP-Signs-Agreement-With-Russian-Drug-Regulator-to-Continue-Developing-Quality-Standards/

http://blogs.law.harvard.edu/billofhealth/2015/10/26/china-to-reform-review-and-approval-process-for-drugs-and-medical-devices/



GMP/INSPECTIONMedicrime Convention Moving Forward

In a press release, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) announced that five of the 24 signatories of the Medicrime Convention have completed their ratification processes of the convention, paving the way for its coming into force on January 1, 2016. The countries completing the ratification process are Hungary, Spain, Moldova, Ukraine, and Guinea. The Medicrime Convention, launched by the Council of Europe in December 2010 (IPQ November 9, 2011), provides for criminal penalties for counterfeiting medicines, marketing medicines without authorization, being non-compliant with conformity requirements or falsifying related documents. Its scope includes drugs and medical devices for human or veterinary use as well as the active substances, raw materials, excipients and components used in their manufacture. The convention directs its signatories to “take the necessary legislative and other measures to ensure that the offences established in accordance with this Convention are punishable by effective, proportionate and dissuasive sanctions, including criminal or non-criminal monetary sanctions, taking account of their seriousness.” Penalties will be applicable to both individuals and corporations.

MHRA MOU with India

In early October, UK’s Medicines and Healthcare products Regulatory Agency (MHRA) announced that it has signed a Memorandum of Understanding (MOU) with India’s Central Drugs Standard Control Organization (CDSCO) that will “increase collaboration between the two countries in the area of medicines and medical devices with the aim of further improving public safety.” Anticipated outcomes include facilitating exchange of information and opportunities for technical cooperation between the agencies. The press release notes that the agreement is similar to those already in place between MHRA and other counterpart bodies in China and the US, although it is a standalone bilateral document. The signing of the MOU took place at CDSCO’s headquarters in New Delhi and was followed by a series of meetings to discuss next steps.

Monetary Penalties for GMP Non-compliance in India

In the wake of drug exports from some firms being banned in the US and the EU, the Indian government is preparing to ramp up its GMP inspections and associated monetary penalties for non-compliance with GMPs, the Hindustan Times reports. In preparation is a WHO-GMP compliant checklist for drug manufacturers and inspectors. Any deviation from the checklist during inspections are likely to attract penalties, which could be double those that are being assessed currently, the article explains. Other penalties could include a ban on exporting, issuance of warning letters, or cancellation of licenses.

Indian Drug Regulator Training

India’s Central Drugs Standard Control Organization (CDSCO) will conduct training in November in Bengaluru and Ahmedabad for its central and state drug regulators on good manufacturing practices (GMP), data integrity and audit readiness, Pharmabiz reports. About 100 drug inspectors, equally divided between CDSCO and the state agencies, are expected to attend. The three-month training program will include experts from regulatory agencies, administrative and police services, the pharmaceutical industry, management institutes and colleges as well as training modules adopted by other regulators. CDSCO also announced in early 2015 that it planned to add 147 new GMP inspectors by the end of the year (IPQ June 27, 2015) to shore up its GMP inspection capabilities. CDSCO also made a proposal to the government’s cabinet of ministers to upgrade the agency’s regulatory oversight using the US FDA as a model, and rename it the Central Drug Administration (CDA) (IPQ June 29, 2015).

Health Canada Bioanalytical Method Validation

Health Canada has responded to its findings of insufficient bioanalytical method validation in some of its applications by providing clarification on its expectations for the validations. In the notice, HC explains that during tests of the stability of drug in biological matrix, some companies have employed the procedure of subjecting only one bulk Quality Control (QC) sample at each concentration to the stability conditions and taking multiple aliquots from that sample.” It refers to a 2012 guidance that instructs sponsors to use sets of “low and high QC samples,” consisting of multiple replicates at each concentration aliquoted prior to the stability experiment with a minimum of three samples subjected independently to the stability conditions that are to be evaluated. For firms that have submitted single sample validations, an amendment to the validation report will be requested that includes stability experiments conducted as described in the guidance.

http://www.ifpma.org/news/news-releases/news-details/article/global-pharmaceutical-associations-welcome-medicri.html

http://www.coe.int/t/dghl/standardsetting/medicrime/default_EN.asp?

http://www.ipqpubs.com/supply-chaingdps/council-of-europe-bolsters-anticounterfeiting-efforts-with-framework-for-criminal-penalties/

https://www.gov.uk/government/news/uk-and-india-regulators-agree-deal-for-closer-collaboration-to-improve-public-safety

http://www.hindustantimes.com/business/pharma-companies-may-pay-double-penalty-for-violating-norms/story-La4fJYc6eVXpdUacyVIfZL.html

http://pharmabiz.com/ArticleDetails.aspx?aid=91170&sid=1



http://www.ipqpubs.com/gmp-enforcement-activity/indian-agency-adding-inspectors/

http://www.ipqpubs.com/gmp-enforcement-activity/india-drug-regulator-upgrades-and-rename/

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/notice_avis_mthd_validation-eng.php

http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/bio/gd_cbs_ebc_ld-eng.php



ANVISA Drug and Biologics Guidelines

The Brazilian Regulatory Agency ANVISA has released three guidelines covering transportation of biological products, process validation, and clinical studies of cancer drugs, pharmaLeaders reports. It notes that the content of the guidelines generally formalizes what had already been current ANVISA practices as opposed to adding new requirements. The guidelines went into effect in early October, but comments will be accepted through April 6, 2016. The guidelines (links are to the documents in Portuguese) are: ● Qualifications for Transporting Biological Products ● Summary of Process Validation for Drug Manufacturing, and ● Outcomes for Clinical Studies of Cancer Drugs.

Taiwan GDP Compliance

The Taiwan Food and Drug Administration (TFDA) has posted a notice (in Chinese) about the phased rollout of good distribution practice (GDP) requirements. According to RAPS Regulatory Focus, TFDA expects the pharmaceutical industry to have fully implemented GDPs by the end of 2018. Taiwan has escalated its push for GDP requirements since becoming a PIC/S member in 2013 and has been actively communicating their importance to industry.

WHO HVAC Guide

The World Health Organization (WHO) has released a draft guidance on GMPs for heating, ventilation and air-conditioning (HVAC) systems for non-sterile pharmaceutical dosage forms, updating the 2011 version contained in the WHO Technical Report Series, No. 961, Annex 5. Changes made in the 2015 version include: ● expanding the “Premises” section and including a number of sample layouts ● aligning the Commissioning, Qualification and Validation (C, Q & V) section with the proposed revisions to the Supplementary GMP Validation TRS937 Annex 4 guideline ● adding a section containing “supplementary notes on test procedures” ● separating out the “Maintenance” section from the C, Q & V section ● revising all the diagrams to achieve better clarity ● adding clarification notes throughout the document, and ● adding a list of abbreviations.

Novartis Closing Indian Plant

Novartis CEO Joe Jimenez said during an October 27 third quarter earnings call that the company plans to close a plant in India, which had received an FDA warning letter the previous day. The company has been working on corrective actions at its Kalwe and Turbhe sites in India since they were inspected in 2014. While not specifying the plant involved. Jiminez said that the inspection on which the warning letter is based is over a year old, and that “a lot of the remediation has already taken place.” He emphasized that there are no supply issues as Novartis continues to ship product from that site.

http://pharmaleaders.com/anvisa-releases-harmonized-guidelines-on-drugs-biologicals/

http://www.fdanews.com/10-15-Anvisa-Guide3.pdf



http://www.fda.gov.tw/TC/newsContent.aspx?id=17170&chk=77235866-45a7-40a1-abfa-df0e2e6337cf&param=pn&cid=4&cchk=f11420b2-cf8e-4d3a-beb5-66521b800453#.Vi5NIX6rSUk

http://www.raps.org/Regulatory-Focus/News/2015/10/27/23476/Asia-Regulatory-Roundup-CFDA-Continues-Medical-Device-Quality-Drive-27-October-2015/

http://www.who.int/medicines/areas/quality_safety/quality_assurance/HVAC_QAS15-639_31082015.pdf

http://www.thestreet.com/story/13341169/1/novartis-nvs-earnings-report-q3-2015-conference-call-transcript.html


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FDA Drug GMP Warning Letters and Recalls Posted in October

Warning Letters

Company Name Location Letter Date Product Type Areas CitedUnited States

St. Clare Health Center

Fenton, MO Oct. 19, 2015

Compounded ● aseptic practices ● smoke studies ● gowning● process validation ● sterilization validation ●environmental monitoring ● batch records ● failure investigations ● SOPs ● labeling

An August 4-14, 2014 inspection of sterile drug compounder St. Clare Health Center resulted in an October 2015 warning letter citing several “serious deficiencies” in its compounding practices “which put patients at risk.” Included in the letter was an example in which the investigator “observed an operator dropping an IV bag on the floor and using it.” The action was in line with the firm’s SOP on aseptic technique, which allows use of medications that have fallen on the floor. FDA said the practice “poses an unacceptable risk of drug product contamination which should be ceased.” St. Clare had registered as an FDA-regulated outsourcing facility twice – both prior to and after the inspection. It was informed by the agency in the letter that the facility “failed to meet the conditions…necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA.” In addition, St. Clare had also failed to submit a list of the drug products that it compounded during the previous 6-month period as required in the outsourcer application. The letter “strongly recommends” that St. Clare “immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation.”

The following are the drug GMP warning letters posted by FDA during October, categorized into U.S. and International. The key concerns that each of the warning letters address and links to the letters themselves are provided. Included are notes on salient features of the warning letter with links to IPQ’s related coverage.

Keynote Speaker – Lawrence Yu – Deputy Director, FDA Office of Pharmaceutical Quality

Other notable topics include Registration

• Quality Metrics • Data Integrity• Combination Products • Biosimilars

Until 1/29/16 = $1199 After 1/29/16 = $1299

• GMP Inspection Trends • International Inspections

Representatives from U.S. FDA, Health Canada, MHRA, Saudi FDA and industry

Workshop on Risk Modeling: The approach to enterprise risk management

For more information go to www.internationalgmp.com

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm469126.htm

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm469126.htm

Jerry

Rectangle

http://www.internationalgmp.com



Recalls

Product Recaller # of Lots

Class Reason

Contamination / Lack of Sterility AssuranceProlotherapy with phenol inj.

Hartley Medical Center Pharmacy

3 I Non-Sterility: Hartley Medical Center Pharmacy is recalling Prolotherapy with phenol due to non-sterility concerns.

All products intended to be sterile

Medistat RX Numer-ous

II Lack of sterility assurance.

Sermorelin lyo powder

DCA Pharmacy One II Lack of Assurance of Sterility: A recent FDA inspection found that this product was not being compounded in an area appropriate for lyophilization, which may lead to a lack of sterility assurance.

Ipratropium/ albuterol inhalation Sol.

Nephron Pharma

2 II Lack of Assurance of Sterility; potential exposure to non-sterile lubricant during the filling process.

Various compounded inj. products

Bedford Pharmacy

13 II Lack of assurance of sterility

Acetaminophen/caffeine

Midway Im-porting

3 II Cross Contamination With Other Products: Potential cross-contamination of cephalosporin.

Bromfenac ophthalmic sol.

Apotex 3 II Lack of Assurance of Sterility: Failed preservative effectiveness testing.

Fenofibric acid tabs

Tribute Phar-ma

30 III Chemical Contamination: The product may contain trace amounts of benzophenone, a component of the label varnish that may leach through the bottle and into the drug product.

DissolutionMetformin ER tabs

Actavis One II Failed Dissolution Specifications: Low Out-of-Specification results for the 8 hour time point.

The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Reports” issued during October. Listed are the generic names of the products, the dosage form, the manufac-turer, the number of lots involved, FDA’s classification, and the specific reason provided by FDA in the Enforcement Report. The recalls are grouped by the general category of problem that caused them. The categories are: ● compliance with NDA/monograph requirements ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/packaging ● foreign product ● particulate ● potency/content uniformity, and ● other spec nonconformance. Within the categories, the recalls are organized by class, with the most serious, Class I recalls at the top.

http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D-1829-2015&w=10072015&lang=eng










http://www.ipqpubs.com/wp-content/uploads/2015/10/Bedford-Pharmacy-recalls-in-October-2015.pdf













Verapamil ER tabs.

Apotex One III Failed Dissolution Specifications.

GMP/GDPFurosemide tabs Boehringer

Ingelheim4 III CGMP Deviations: The active pharmaceutical ingredient

(API) intended for use in furosemide oral solution USP was inadvertently used to manufacture the recalled furosemide tablets USP

ImpurityEtomidate inj. Hospira One III Failed Impurities/Degradation Specifications: Out of

Specification (OOS) results for degradation product of etomidate was confirmed during stability testing.

Labeling / Packaging

Pain relief patch Mentholatum 4 II Labeling: Incorrect Instructions; The word “not” is missing from the following sentences “do bandage tightly or cover with any type of wrap except clothing and “do use with a heating pad or with other heat sources” in the Drug Facts panel “Warning” section.

Donnatal Rx PAK 2 III Labeling: Not elsewhere classified - Product label incorrectly lists Scopolamine Hydrocodone as an active ingredient on the side panel instead of Scopolamine Hydrobromide.

Metoclopramide oral sol.

VistaPharm One III Defective Container: Lids on unit dose cups are not fully qualified

Foreign Product

Ezetimibe/ simvastatin tabs

Merck One II Presence of Foreign Tablet/Capsule: Vytorin 10 mg/40 mg tablets were found in bottles of Vytorin 10 mg/20 mg tablets

Potency / Content Uniformity

Lipo B inj. Eagle Pharmacy

One II Subpotent Drug: trace amounts of methylcobalamin in compounded drug.

Loratadine tabs. Ohm Labs 129 II Superpotent Drug: Out Of Specification (OOS) result for assay.

Urofollitropin inj. Ferring Pharma

7 III Subpotent Drug: Stability samples were confirmed to be out of specification for potency at the 12 month time point.

Topical acne medication

Guthy-Renker 28 III Subpotent Drug: Salicylic acid is subpotent.

Other Spec NonconformanceMethylphenidate transdermal system

Noven One II Defective Delivery System: Out of specification for z-statistic related to mechanical peel force.

http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D1834-2015&w=10072015&lang=eng

http://www.accessdata.fda.gov/scripts/enforcement/enforce_rpt-Product-Tabs.cfm?action=select&recall_number=D1834-2015&w=10072015&lang=eng










http://www.ipqpubs.com/wp-content/uploads/2015/10/Ohm-Lab-recalls-in-October-2015.pdf







www.usp.org

Adulteration and Fraud in Food Ingredients and Dietary Supplements: Attend Two Key Learning EventsDecember 2, 2015 - December 4, 2015

In-vitro Testing for Future Challenges for Veterinary Dosage FormsMarch 14, 2016 - March 15, 2016

USP's Controlled Room Temperature Definition: Is it time to expand the temperature range?May 23, 2016 - May 24, 2016

12th Annual International Symposium on Pharmaceutical Reference Standards Co-sponsored by: EDQM, Council of Europe and USPNovember 3, 2016 - November 4, 2016

Single Use Systems: Development of a Compendial StandardJune 20, 2016 - June 21, 2016

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MONTHLY U OCTOBER 2015...of the number of batches used in the PPQ runs a state of control, referred...

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