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EDITOR’s NOTE: Welcome to IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications includes “The News in Depth” and”Updates in Brief” on our website as they occur, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” IPQ’s suite of offerings support our mission of helping read-ers understand, engage in and respond to the dialogue and developments around evolving and harmonizing the regulation of drug and biologic quality and manufacturing. Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further information.

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MONTHLY UPDATE - JUNE 2012

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INTERNATIONAL PHARMACEUTICAL QUALITYInside The Global Regulatory Dialogue

VOL. 3, NO. 5

CMC/REVIEW

• Human Factors Need to Be Studied for Pre-filled Syringes 2 • Post-Change Comparability, PEGylation Among Biotech CMC Issues Addressed at AAPS NBC........................................5 • QbD at Vertex

Role in Formulation and Manufacturing Cited..................9 New Course Charted with CMOs......................................19

Bio-Modeling, Continuous Manufacturing on Agenda 26 • IQ Consortium Spins Off Lab Interlinking Effort.................31

INTERNATIONAL CMC/REVIEW

• WHO Imprimatur, Overhauled Regulatory Structure Could Push China To Global Vaccine Prominence.............47

UPDATES IN BRIEF - p. 49

ISPE Mission Refinements • MHRA and EMA In-spection Results • Release Testing in EU for Russia

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FDA Expectations for Studying Human Factors in Pre-filled Syringes are Taking ShapeFDA is increasing its pressure on sponsors to conduct pre-market human factors (HF) studies for combination pro-ducts, including pre-filled syringes, and industry is getting clearer on the agency’s expectations as more experience is gained.

At the AAPS National Biotech Conference in late May in San Diego, California, Douglas Mead, the Regulatory Affairs CMC Director for Medical Device and Combination Products at Janssen Biologics, confirmed that the Center for Drug Evaluation and Research (CDER) is now “requiring formal summative human factors studies for most delivery devices.” CDER, he added, is requesting that human factor study protocols be “sent in for review prior to implementation.”

Human factors/usability analysis has been gaining prominence in the dialogue between combination product manufacturers and regulators.

At issue is an effective pathway for companies to follow in conducting and submitting the analysis and for regulators to follow in reviewing it. (See IPQ “Monthly Update” April 2011, p. 12. The story includes insights by Center for Devices and Radiological Health (CDRH) Office of Device Evaluation (ODE) Ron Kaye, who leads the office’s Human Factors and Device Use Safety Team.)

At the AAPS meeting, Mead discussed the experience Janssen and other firms are gaining regarding: ● what information the agency is looking for, when it is required and in what

form ● general study requirements ● expectations for Phase III clinical trials, and ● challenges posed by biologics when conducting human factor studies.

FDA Wants to Pre-clear Protocols

CDER wants HF protocols to include “the current instructions for use and some summary information for the actual user risk analysis that was used to determine which critical tasks in the use of your product you are going to assess in these protocols,” Mead explained.

“I know from my own experience and from my industry colleagues that at least six requests from FDA have been made to submit human factor study protocols in the last year” for prefilled syringes, he commented.

The Janssen official characterized the agency’s effort as applying the design validation aspects of medical device design controls to a drug product.

The “essential aspects” that the agency is looking for include a user task analysis based on the instructions for use (IFU) and identification of the critical tasks that need to be conducted.

One or more “formative studies” – the “practice runs” for human factor studies – should be conducted. During the conduct of the studies, the sponsor “can interact with the subjects and understand their thinking, what they are confused about and what design characteristics of your device are problematic.”

http://www.ipqpubs.com/issues/ipq-monthly-update-april-2011/http://www.ipqpubs.com/issues/ipq-monthly-update-april-2011/http://www.ipqpubs.com

MONTHLY UPDATE - JUNE 2012 MONTHLY UPDATE - JUNE 2012 MONTHLY UPDATE - JUNE 2012

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INSIDE THE GLOBAL REGULATORY DIALOGUE™

Following the formative studies, a “summative study” is conducted, which is similar to a clinical trial pivotal study, “where you provide the instructions that you intend to go to market with and see, with no intervention, whether the subjects can use the product,” Mead explained.

The studies are generally requested by CDER during a “Type C meeting” or an “end-of-Phase II meeting” in response to the sponsor stating that a usability study is planned.

At that point, the agency has been requesting submission of HF study protocols. If the request is made by CDER, it “will confer with the device experts at CDRH, who will look at it from a human factors standpoint, and they will get back to you with comments within 30-60 days,” Mead pointed out.

He characterized submission of the protocols as “generally a good idea, because you want some input at that point before you do the study to see if the study methodology would be acceptable to them ultimately when you are seeking approval.”

Mead commented that the reviews are generally thorough and helpful.

The agency is looking to ensure that identification of critical tasks and a user FMEA have been conducted, and examining how those are reflected in the user instructions.

“In other words, what are the controls? What are you comparing?” Mead asked. The sponsor may be looking only for confirmation of usability, but what studies actually get performed and submitted are negotiated with the agency.

In turn, FDA is still working on “the process they are going to use to approve or provide informal feedback on these protocols and what they will accept at the end.”

FDA Guidance Addresses Subject Involvement

The Janssen official pointed out that FDA has a “very good” draft guidance that explains its expectations for human factors studies. The draft, issued in mid-2011 by CHRH, addresses the applicability of “human factors and usability engineering to optimize medical device design.”

One of the issues on which clarification is provided is the number of subjects and subject groupings that an HF analysis should encompass. “A minimum” of 25 test participants is recommended.

“That does not mean just 15-25 subjects – it means per group,” Mead emphasized. “So, for an autoinjector study, you may define a group that has an impairment, a group that does not have any impairment, a group that is comprised

of healthcare providers in a home setting, and a group of patients in a home setting. These groups can be any way that you decide to define them.”

This is “an important point,” he emphasized. “If you just limit it to 25 subjects and they all pass, you would seem pretty satisfied. However, you have to deal with actual field experiences. Say you take 100 subjects and 99% of them can use an autoinjector with no problem at all. When you look at your complaint rates in a marketed product, multiply that 1% of user difficulty by a million autoinjectors on the market and you will see that you have a very high complaint rate. So this only gives you a feel for what your success in the market will actually be.”

Mead pointed to the uncertainty that exists in the studies and their inability to predict what may actually happen once the product is marketed.

“All kinds of things can happen,” he stressed. “We need to consider human behavior and startle reactions. It is not always predictable. Human factors studies will not actually tell you what is going to happen in the field perfectly.”

One tact Janssen has pursued to aid with user understanding was “an autoinjector trainer to make sure that patients were very familiar with autoinjector functionality.”

Phase III and Biologics Expectations Taking Shape

Two issues that have been drawing attention in the HF arena are the drug-device presentations that should be used in Phase III and bioequivalence considerations, particularly in the biologics context.

“New on the table,” Mead pointed out, is a move by CDER to “require the final to-be-marketed presentations to be used in some way in the Phase III trial.” While doing so is not a substitute for a human factors study, the final configuration is expected to “be assessed in a clinical trial in some way.”

Mead noted that there is a heightened concern with bioequivalence data in the US.

“In Europe, they have a bioequivalence guideline that says that for a single mode of administration you really only need to do, for example, subcutaneous injection – [that] if you have a prefilled syringe or an autoinjector, it really doesn’t raise a bioequivalence question.”

Complex biologic products, he noted, present unique challenges in assessing the bioequivalence implications of usage variations.

As the patient response to biologic products can be “highly



MONTHLY UPDATE - JUNE 2012variable,” it is challenging to determine in a bioequivalence study “whether any differences you saw were related to a statistical nuance of patient variability or were actually related to differences in the devices.”

In these cases, a number of questions can confound the results – for example, “is the depth of injection the same? Are you compressing a fat layer differently?”

Comparing the US and European requirements, Mead noted that “on a practical basis, those things are not considered in Europe, where they believe that sub-C is sub-C.”

DOWNLOAD FROM THE STORY:

• FDA Draft Guidance on Human Factors and Usability

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Analysis of Post-Change Comparability and PEGylation Among Biotech CMC Concerns Drawing FDA Comment at AAPS National Biotech ConferenceThe expectations for pre- and post-change lot comparisons and for PEGylation analysis were among FDA CMC application filing concerns addressed by CDER Office of Biotechnology Products (OBP) official Susan Kirschner at an “ask the regulator” session at AAPS’ National Biotech Conference in late May in San Diego, California.

Intended to probe into some of the issues on which firms are looking for more clarity in putting together CMC applications for biotech and other biological products, the questions to which Kirschner responded had been submitted to FDA in advance of the meeting by the AAPS’ Protein Aggregation and Biological Consequences Focus Group.

In addition to OBP’s expectations for comparability studies and PEGylation, the focus group sought clarification regarding: ● the promotion of new analytical technologies ● preference of technologies for examining sub-visible particles ● surfactant specifications ● stability testing of sterile filtered bulk drug product ● the use of disposables in manufacturing ● assessment of leachable accumulation, and ● expectations for characterization of what happens to biomolecules after injection.

While some of the questions were not the type that lend themselves to easy answers, Kirschner made an effort to give succinct responses and to summarize current agency thinking on key areas of concern. She serves as Associate Chief of OBP’s Immunology and Therapeutic Proteins Laboratory. [Kirschner’s responses to all the questions posed by the AAPS committee are provided below.]

Compare Pre/Post-Change Lots Side-by-Side

Kirschner stressed that data from stability and degradation studies of various types and side-by-side comparisons between pre- and post-change lots were key elements that the agency looks for in comparability studies.

Depending on the change, extended characterization studies/data, real-time stability data, accelerated temperature and/or forced degradation studies may be required. “Forced degradation studies are less likely,” she commented. Stressed and accelerated degradation data “can be important to understanding the kinetics of degradation…that may reflect some change in your molecule that wasn’t picked up otherwise.”

Kirschner explained the agency’s expectation for side-by-side analyses of pre- and post-change lots.

“If you are running an SDS-PAGE gel, it is really hard if you have different gels or gels from different time periods to compare the data. So it is really good to have those in side-by-side analyses.”

Recognizing that there are generally fewer post-change lots available than pre-change lots, the CDER official emphasized the importance of putting post-change data in the context of the pre-change data. “That usually occurs in the form of control charts or some kind of trending data.”

CDER is “looking to see if you are within trend or if there is some indication that there has been a shift in a particular product quality attribute. That has in some cases required additional post-change data to see if there has truly been a shift and what that shift may mean. If you have gels and chromatograms, we would like to see pictures of them for multiple pre-change lots and some post-change lots to put everything into context.”

PEGylated Products Require Detailed Analysis

CMC applications for PEGylated proteins – those that contain chemically-bonded polyethylene glycol (PEG) to enhance structure and/or function – should include detailed characterization of both the molecule and the PEG used to produce it.

“PEG is a raw material and should be characterized,” Kirschner emphasized. She explained that it is important to examine the purity of the PEG – in particular, the chemical residuals from the manufacturing process that may need to be removed. “Some PEG manufacturing processes involve the use of cyanide, so you want to measure the cyanide levels. You should also look at the structure of the PEG…and the level of activation.”

The agency also expects an analysis of how and where PEG is incorporated into the active pharmaceutical ingredient (API).

The CDER official stressed the need to “look at the number of sites that are occupied by the PEG, where those sites are, and what the level of occupancy is at any given site during the process.” She added that “we have seen that…even some subtle changes in levels of site occupancy can impact PK. So these are not just ‘nice to knows,’ they are really ‘need to knows’ for PK purposes.”

Also recommended is quantitation of the free PEG in the product and evaluation of the stability of the PEGylation. “We have seen some products where the bond between the PEG and the protein is not stable, and over time they separate. So you have to look at that too.”

DOWNLOAD FROM THE STORY: • CFR Amendment on stability test requirements for biological products

https://www.federalregister.gov/articles/2012/05/03/2012-10649/amendments-to-sterility-test-requirements-for-biological-products



MONTHLY UPDATE - JUNE 2012CDER’S SUSAN KIRSCHNER ON BIOTECH CMC QUESTIONS

Q: What is the approach taken by FDA to evaluate a comparability study?

Of course, there is ICH Q5E [“Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process”] that we follow. Our main interest is whether it impacts drug substance and/or drug product. Depending on the change, this may require extended characterization studies or data, real-time stability data, stressed accelerated temperature and/or forced degradation studies. Forced degradation studies are less likely. Stressed and accelerated degradation data can be important to understanding the kinetics of degradation of a change that may reflect some change in your molecule that wasn’t picked up otherwise.

You really should have side-by-side analyses with pre- and post-change lots. If you are running an SDS-PAGE gel, it is really hard if you have different gels or gels from different time periods to compare the data. So it is really good to have those in side-by-side analyses.

Generally there are fewer post-change lots available than there are pre-change lots, but we would like to see the post-change data put in the context of the pre-change data. That usually occurs in the form of control charts or some kind of trending data. There we are looking to see if you are within trend or if there is some indication that there has been a shift in a particular product quality attribute. That has in some cases required additional post-change data to see if there has truly been a shift and what that shift may mean. If you have gels and chromatograms, we would like to see pictures of them for multiple pre-change lots and some post-change lots to put everything into context.

Q: How does FDA decide when to ask for data from new technologies?

First and foremost, safety is a critical driver. For example, analysis of sub-visible particles was driven by a concern over immunogenicity. The impact of immunogenicity of sub-visible particles was really what drove pushing those technologies.

The other reasons that we may push for implementation of new technologies is better characterization for product knowledge so that you can understand product quality attributes and how process changes may impact those quality attributes. Again, that would be at the characterization level, not for release.

We do sometimes push including new technologies for in-process and release tests because they are more accurate or sensitive or better resolve differences, like electrophoresis methods. We have pushed including new technologies when we think that the technology the company is using has become too outdated or is not informative enough.

To push something to be an in-process or release test, the technology has to be ready for implementation in a GMP environment. So sometimes there is a lag when you put something in for characterization studies and when you might start incorporating it into in-process and release testing, because it was just not ready for GMP requirements yet.

Q: Does FDA prefer a particular technology for looking at sub-visible particles?

The answer is no, not right now. If it falls between the 0.2 to 10 micron range, the nature of your particles need to drive the technologies most suitable for your situation. Most companies use size exclusion HPLC below 0.2 microns and light obscuration above 10 microns. That is a choice, not a requirement, with the exception of parenterals, for which there is a particulate matter requirement above 10 microns of using light obscuration, which is in one of the recommended USP methods.

At the AAPS National Biotech Conference in late May in San Diego, California, CDER Office of Biotech Products Laboratory of Immunology and Therapeutic Proteins Associate Chief Susan Kirschner pro-vided answers to a set of CMC questions submitted in advance of the meeting by the AAPS Protein Aggregation and Biological Consequences Focus group. The group sought clarification from OBP on: ● submission and evaluation of process changes and comparability protocols ● promotion of new analytical technologies ● preference of technologies for examining sub-visible particles ● surfac-tant specifications ● evaluation of PEGylated products ● stability testing of sterile filtered bulk drug product ● the use of disposables in manufacturing ● assessment of leachable accumulation, and ● expectations for characterization of what happens to biomolecules after injection.


JUNE 2012 7


That specific number [0.2 micron] comes from where the gap really starts. In most size exclusion chromatography analyses there is a 0.2 micron filter. Anything larger than that tends to get filtered out in those analyses.

USP starts at 10 micron, so most people were collecting data at 10 microns and above. But nobody was really systematically collecting between 0.2 and 10. That is where the range comes from – that is the range that wasn’t being measured.

Q: At which clinical phase is surfactant specification required? If we can demonstrate stability over a range of surfactant concentrations, is it still required to have surfactant content in the specification?

There are clearly different interpretations and approaches to this question. Thinking about the surfactant being one of the excipients – as an excipient you would have to know how much is in the product, and you should test for it. It could potentially be in the bulk drug substance or the final dose product, depending on when you know the level of the surfactant.

You cannot just raise your surfactant level without knowledge, or else you have the potential to impact PK/PD and clinical safety and efficacy, not just product stability. You can’t just change your surfactant because the product is stable. If the same excipient is present in different amounts in different lots, then those are considered different formulations.

Q: What are the regulatory recommendations for PEGylated products?

Actually the original question said regulatory ‘hurdles,’ and we changed it to recommendations, because I don’t think there are any regulatory hurdles.

PEG [polyethylene glycol] is a raw material and should be characterized. PEG has a range of size distributions, so you should know that. You should look at the purity – in particular, the chemical residuals from the manufacturing process that may need to be removed. Some PEG manufacturing processes involve the use of cyanide, so you want to measure the cyanide levels. You should also look at the structure of the PEG.

There are other things you might want to do for qualification as a raw material as well, depending on what your specific needs are. Sometimes PEG gets activated, so you might want to look at the level of activation.

For the bulk drug substance we also have requirements. You should look at the number of sites that are occupied by the PEG, where those sites are, and what the level of occupancy is at any given site during the process. We have seen that…even some subtle changes in levels of site occupancy can impact PK. So these are not just ‘nice to knows,’ they are really ‘need to knows’ for PK purposes.

You should look at the amount of free PEG in your product and see whether or not you are going to remove it. And then the stability of the PEGylation is important. We have seen some products where the bond between the PEG and the protein is not stable, and over time they separate. So you have to look at that too.

Q: What is the need for stability testing of sterile filtered bulk drug product if in-line filtration is used?

We don’t actually review this in our group, so we checked with our counterparts in the biologics manufacturing and assessment branch, which does the micro reviews for BLAs as well as facility inspections.

Effective May 3, 2012, the CFR has been amended regarding the use of specific sterility tests, sample size requirements and the need for sterility testing of bulks. So a lot of those requirements have been removed or amended. You should check the Federal Register to see how that applies to your particular product.

On stability, we really prefer container closure integrity tests rather than stability testing as it is a better measure of what your container closure is capable of rather than whether any particular vial was actually contaminated.

Q: Do disposables bring more safety or risks into bioproduction? Is there a platform approach to leachables testing?


WWW.IPQPUBS.COM JUNE 2012 8

MONTHLY UPDATE - JUNE 2012 Disposables can increase safety. If you have a multi-drug facility they could help eliminate cross contamination. If you have particularly dangerous products like toxins, it may be very useful to use disposables. However, there are different risks so far as leachables and extractables are concerned…. The leachables may increase or decrease any particular risk, but they are different and you need to understand them.

The other question is whether you can use a platform approach. We have seen cases where you can use model media, which may give you some reasonable idea of what your leachables are. However, the protein itself can impact the leaching process. Most importantly, there is some concern about the toxicity in and of itself of a leachable. Most leachables are not present in levels that are toxic to humans but are present in levels that can degrade product or impact product quality.

From that standpoint, if you are looking at platforming, you have to understand how the leachables impact your product. And that isn’t really easily platformable, unless it is something that is really like the drug product…with maybe only a change of a few amino acids.

Q: Is an assessment of leachables accumulation while using multiple products required?

FDA generally considers that leachables assessment of bulk drug substance and final product reflects accumulation during the process that should be removed by diafiltration steps or other means. In-process hold time studies may also incorporate assessment of leachables accumulation depending on how they are designed.

We have not yet asked for specific studies to look at accumulated leachables all along the way and look at them specifically in that manner.

Q: How concerned is FDA currently as regards the use of silicone to lubricate packaging components – do we now have some regulatory relief?

Probably not. FDA is concerned with silicone because of its ability to nucleate aggregation. FDA expects aggregates to be assessed, and to the extent possible, characterized. So during that process for which there is no regulatory relief at this point, you will be looking at your silicone.

Siliconization is required for syringes to function. So you need to assess your syringes for their consistency and levels of coverage to ensure consistent syringe function and also for the stability of the syringe function. So I don’t see how we could get away with providing regulatory relief on those kinds of assessments.

Q: What are the regulators’ expectations as regards characterization of what happens to the biomolecule (aggregation, binding to local/plasma proteins, degradation, glycosylation) after injection or infusion? Is there a set of standard tests available or planned to be made available? Are there specific in vitro models or assessments FDA prefers?

There isn’t an actual regulatory requirement to look at that. We do consider it useful information when you are thinking about product stability and product quality attributes and setting limits.

These studies are really difficult to do. It is something we are interested in, particularly the subcutaneous space, and whether or not your product generates aggregates in that space when you inject, and whether that impacts immunogenicity. So while we would love for people to do those studies and be happy to look at them and review them, we haven’t been requiring them.

There were also some questions about antibody-drug conjugates. But I couldn’t get anybody from the Division of Monoclonal Antibodies here, so I can’t talk about it.

What I can say is that antibody conjugates are reviewed as a collaborative review with the Office of New Drug Quality Assessment looking at the drug part and the Division of Monoclonal Antibodies looking at the monoclonal antibody part. They work very closely together. They are complicated products and complicated reviews.

http://www.cmcbio.comhttp://www.cmcbio.com


JUNE 2012 9


Vertex Harnesses QbD to Solve Difficult Formulation and Manufacturing IssuesVertex’ experience with the development and approval of its oral solid hepatitis-C drug Incivek (telaprevir) testifies to the power of quality by design (QbD) to help solve the problems posed by molecules that are difficult to develop, formulate and manufacture.

At a symposium sponsored by the International Consortium for Innovation and Quality in Pharmaceutical Development (“IQ Consortium”) in December in Cambridge, Massachusetts, Vertex Senior VP for Pharmaceutical Development Patricia Hurter commented on the close collaboration and cross-discipline efforts that were needed to address the QbD challenges and bring the development and commercialization process for Incivek to completion.

“Pharmaceutical development, which I am the head of, regulatory, technical operations and quality lived in each other’s pockets for months,” working together to solve the technical and communication problems, the Vertex official said. “I think being a small company helped us to be able to do that.”

In her presentation, Hurter discussed: ● Incivek development and characterization ● understanding chemical stability ● advancing the science of spray drying ● scaling down for new projects, and ● the firm’s QbD filing.

Hurter also spoke about Vertex’ focus on biopharmaceutics modeling and continuous manufacturing as potentially powerful tools for advancing its drug development and quality by design (QbD) program (see the story on p. 26).

[Editor’s Note: A third story in IPQ’s series on Vertex focuses on the communication pathways that had to be created with its contract manufacturing partners to achieve its Qbd objectives—see story on p. 26]

Incivek, approved in May 2011 under a six-month review clock, is Vertex’ first drug on the market. Approval of a second QbD-based application followed in January 2012 for Kalydeco, a drug for treating cystic fibrosis. In a speech delivered in February, FDA Commissioner Hamburg touted Kalydeco as the first drug to “treat the underlying mechanism of the disease rather than the symptoms” (see IPQ “Monthly Update” March 2012, p. 2).

Vertex currently has around 2,000 employees and uses contract partners to do all of its clinical and commercial manufacturing, from bulk production through final packaging. The primary drug substance manufacturer with whom Vertex has been working is Hovione, which has been

an important contributor to the overall QbD effort.

Solubility and Bioavailability Problems Addressed

Hurter explained that Incivek is large for a small molecule, at 680 Daltons. She characterized it as a “very complicated” and “extremely challenging” molecule with low solubility and low bioavailability.

Telaprevir is “actually less soluble than marble,” she noted, and finding a model for how to formulate it to get acceptable bioavailability was “challenging.”

From solution, the bioavailability was about 2%; from a crystalline suspension, 1%; and from a nano-suspension, 1.7%. By creating “tight dispersions with different types of polymers,” the bioavailability was increased to around 20% or 40% in rats. “That was hugely promising,” Hurter stressed. “So that was the path forward that they took.”

The initial amorphous formulation had a “limited tendency to crystallize a bit too rapidly,” so Hurter’s group developed a more physically stable formulation “that improved exposures dramatically” and became the formulation used in the marketed product.

When telaprevir was first dosed in man in 2004, the toxicity was “lower than expected,” but exposure data was highly variable.

An investigation into the reason for the variable exposure data indicated that the original stability studies performed on the suspension had likely overestimated the stability time, that dosing was performed near the end of the stability time, and that the amorphous drug product appeared to be crystallizing.

Vertex scientists performed X-ray powder diffraction, solid state NMR, thermally-stimulated current, differential scanning calorimetry and solubility tests, but were unable to discover why the material was crystallizing.

Testing with isothermal titration calorimetry, a technique used in research to determine drug-protein binding constants, revealed that the telaprevir suspension was crashing – changing from amorphous to crystalline form over time – with a transition time of about four-and-a-half hours.

The “induction time” – how long after the suspension is prepared before it begins to crash – was found to decrease

http://www.ipqpubs.com/news/fda-commissioner-hamburg-highlights-the-role-of-fda-and-regulatory-science-in-drug-innovation/



MONTHLY UPDATE - JUNE 2012as the storage temperature went up.

As a short-term solution, the firm decided to refrigerate the suspension until it was time to dose. That action was shown to improve the physical stability.

For a longer term solution, different polymers were investigated for use in the dispersions, eventually leading to the formulation that was used in the final commercial product, which stayed 100% amorphous for at least 72 hours at 37°C.

“Once we got the physical stability nailed, we thought we were good,” Hurter reported. “Then we discovered that we had a really bad chemical stability issue, which basically meant that we would have to have a refrigerated product, which is really not very cool. Nobody wanted to have a refrigerated product.”

Excipient Impurities Impact Chemical Stability

“Huge” lot-to-lot differences in the stability of telaprevir were investigated using accelerated stability tests conducted at 40°C and 75% relative humidity in an open dish. The differences in the rate of lot-to-lot degradation were asso-ciated with the use of different lots of a particular excipient.

After much experimentation, the differences seen were traced to the slurry pH of the excipient, and its variability to a residual impurity from the excipient manufacturing process.

Vertex worked with the excipient manufacturer and found that the impurity level had increased over time. “What had happened was that they had allowed their process to kind of drift off in a region where they weren’t washing the excipient at the end quite as well. By instituting a better washing procedure they were able to bring the impurity down again.”

Vertex “set specifications and had the supply chain folks negotiate an ordering spec at 100 ppm, even though our proven acceptable range was up to 300 ppm,” Hurter explained. “In my mind, this all worked together to produce an excellent result.”

The Vertex VP emphasized that solving the stability issue required collaboration between a large num-ber of individuals and disciplines.

“We had good collaboration between formulation, analytical and process chemistry, who helped figure out what the degradation mechanisms were from studying the molecule. Materials characterization experts helped with all the differ-ent things that we did to characterize the excipient. Technical operations handled the packaging and the controls in the

manufacturing. Together they determined the root cause of the instability and developed models to predict stability.”

Advancing the Science of Spray Drying

Because telaprevir is an amorphous product with a high melting point, spray drying is required to produce the final API.

During development of Incivek, Vertex developed a “huge” spray-drying database, with 162 data points from two similar models of commercial scale spray dryers – “the one that was originally there and the one that was built,” the Vertex VP explained.

“We did a total of 13 DoEs over three years to generate the database. It was an awful lot of money, time and effort. Some of the stuff that was made was used as clinical material, so it wasn’t all development. It was a huge investment, and we wanted to be sure to make the best possible use of the investment.”

Hurter reported that Vertex is collaborating with Bend Research, a firm that specializes in spray drying and has published papers and given presentations regarding a concept called “heat and mass transfer ratio,” or HMT. HMT relates the speed of spray drying to the properties of the material produced.

“When I heard about this, I thought that it was fantastic,” Hurter commented. She reasoned that Vertex could use the data from its database, calculate HMT ratios, and run the calculated conditions to produce product with better particle size control.

However, what she observed was variability in the HMT ratio correlation as well as some variability between spray dryers.

In discussing the results with Bend, Vertex discovered that Bend’s research had all been done with constant droplet size, whereas Vertex’ database contained data resulting from varying a variety of parameters, including droplet size.

Although Hurter admitted that “there are still things that we need to understand about how to control these spray dryers and how to collect the data that we haven’t figured out yet,” in the case of telaprevir the work has led to a process that is “under excellent control with really consistent control of particle size and bulk density.”

New Projects Require Smaller Scale

One of the “major reasons” Vertex is working with Bend is to try to figure out how to scale down for new projects


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and address the differences between its various spray dryer equipment models.

Vertex deployed a small scale dryer in its initial development work, and then graduated up to a larger capacity model. “As we changed the scale of the spray dryer we had much more drying time and nozzle changes,” as well as different relationships between particle size and bulk density, the Vertex official explained.

Vertex worked with Bend using a custom spray dryer nozzle test apparatus that allows it to take nozzles from other firms’ spray dryers and measure the droplet size as a function of atomization pressure.

Bend was able to perform the measurements on Vertex’ various spray dryers and predict the atomization pressure that would reproduce the desired droplet size between equipment.

Using the data produced, Vertex was “able to get right in the region we wanted to be in” and reproduce the desired droplet size on its various scale spray dryers.

Hurter praised the contribution of QbD in creating a “flat line” process.

All the QbD work the company did with telaprevir has resulted in the production of “tons of product with high quality and low variability.”

QbD Filing Proves Challenging

Vertex’ new drug application (NDA) for Incivek was the first the company had filed. In addition, it was the first full QbD filing FDA had received for a product containing a complex molecule with a complicated synthesis and extended supply chain.

The QbD filing was “a little bit ambitious,” Hurter admitted, as the product is “complicated in every way—from an analytical standpoint, from an API standpoint, and from a formulation standpoint.”

The virtual manufacturing process involves multiple players in diverse geographic locations, she pointed out.

“We make API in one place and then we ship it somewhere else, to a different continent, to spray-dry it to make the amorphous stuff. Then we ship it somewhere else to a different continent and we make tablets and film coat

them. Then we ship it somewhere else to be put in blister packaging cartons.”

She pointed out that with all activity outsourced, Vertex had to oversee the QbD implemention at manufacturing plants “that we don’t control” (see the story on p. 19).

Another challenge in the QbD arena was an odd-shaped design space that proved “very difficult” to explain to FDA.

“Because we had a square-shaped design space with one corner cut off, we had to represent the specification with an equation – very challenging to explain to the agency,” Hurter noted.

Vertex Introduces Model Updating Mechanism

Adding another element to the QbD dialogue with FDA was Vertex’ introduction of an “allowable model bias” (AMB) concept that reflects the uncertainty inherent in the initial model and allows it to be refined as more experience is gained.

For example, the AMB concept would allow a particular spray drying operating parameter to be redefined as more data is generated.

“You don’t want to keep using the wrong model to control the spray dryer,” Hurter emphasized. “You want to be able to refine your models to reflect what you now believe is the truth.”

She pointed out that FDA is “fully in favor of what they call ‘model maintenance,’ but when you actually ask how that is supposed to be done, nobody has a clue. So we came up with the AMB.”

Hurter recounted that during a pre-NDA meeting when Vertex was explaining the AMB concept, FDA asked for a literature reference that explained how it was arrived at and defined.

“We told them there wasn’t one – we made it up. They looked at us like we were a little bit crazy. So we said that we need to publish it so we can reference ourselves.”

Coming up with ways to do model maintenance that everyone can buy into “is one of the things that I am hoping the IQ Consortium can help with,” Hurter emphasized. [Editor’s note: An update on the IQ Consortium’s progress to date is provided on pp. 38-45]


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MONTHLY UPDATE - JUNE 2012VERTEX’ PATRICIA HURTER ON INCIVEK PROCESS AND PRODUCT DEVELOPMENT

CHALLENGES

We talked this morning about how innovation is all about culture. I completely agree with that. You have to make sure it is not a program. It should be a way of just being.

Vertex has a pretty unique culture…. The company’s whole purpose is to ‘innovate to redefine health and transform life with new medicines,’ which is a pretty lofty core purpose.

The first of three Vertex values that go along with that is ‘fearless pursuit of excellence.’ I really like that one. Basically it says that you have the ability to take risks and not be afraid. In my experience at Vertex we have done some pretty risky things. And when the stuff has hit the fan, so to speak, people did not come down on you like a ton of bricks – they said, ‘OK, what is plan B? Let’s move on.’

The second one is ‘innovation is our lifeblood.’ I think that kind of speaks for itself – we are very in favor of innovation. My boss, the chief scientific officer, is probably the most innovation-friendly person I have ever met in my entire life. He encourages people to be innovative, which I think is great.

The third one is ‘we wins.’ Initially when I heard these three, I liked the first two, and the third one sounded a little boring, like playing nice in the sandbox, which didn’t seem that exciting to me. But when it was explained more fully, ‘we wins’ means innovation happens at the vertices. It means that success is not singular. Success is when people get together. And the fact that innovation happens at the vertices means that basically we have people from different backgrounds – different academic training, different countries, different genders, people of different, diverse backgrounds. And when you put them together that is when you get innovation.

I am going to try to give you some examples of collaboration across traditional boundaries – between research and pharmaceutical development, between the company and contract manufacturing organizations, between us and the regulators – where we get innovation.

I am going to go through three things: ● development of Incivek and some areas where collaboration drove innovation ● progress we are making on biopharmaceutical modeling, and ● where we are heading – continuous processing. Don’t worry that the first one takes a while because the second two are much shorter.

2011 was really exciting. We filed our first new drug application in the US in November 2010, and got approval in May 2011. It was followed by approval in Canada, Europe and Japan shortly thereafter.

Incivek is an amazing drug. It cures people of hepatitis C, which is a serious worldwide health problem. It is the first drug that Vertex has taken all the way to market by themselves, after being in business for 21 years and having spent about four billion dollars.

We also filed our first NDA in late 2011 for cystic fibrosis. To have two NDAs back-to-back, the first ones the company has filed, in less than a year, was obviously quite a challenge.

Incivek Characterization

Incivek – which is also known as telaprevir – is actually an extremely challenging molecule. It is supposed to be a small molecule, but it is not that small – it is 680 Daltons.

At a symposium sponsored by the International Consortium for Innovation and Quality in Pharma-ceutical Development (IQ Consortium) in December in Cambridge, Massachusetts, Vertex Senior VP for Pharmaceutical Development Patricia Hurter detailed the product and process development, for-mulation and filing challenges her firm overcame with its hepatitis-C drug, Incivek (telaprevir). In her presentation, entitled ”Innovation Happens at the Vertices,” Hurter discussed: ● Incivek development and characterization ● understanding chemical stability ●, advancing the science of spray drying ● scaling down for new projects ● remaining opportunities, and ● the firm’s QbD filing.


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It is very complicated. It has a high surface area and high logP [octanol-water partition coefficient, a measure of hydrophobicity]. It is incredibly insoluble – 4.7 micrograms per milliliter. The main reason is that it is highly crystalline with a high melting point of 246°C.

Telaprevir is actually less soluble than marble…. Finding a model on how to formulate it to get good bioavailability, needless to say, was challenging. Before I joined Vertex, a very creative and innovative formulation development group tried absolutely everything. It was a small group with limited resources, but they tried everything to get this molecule to be bioavailable.

From solution, the bioavailability is about 2%; from a crystalline suspension, 1%; and from a nano-suspension, 1.7%. But they found that when they made pretty tight dispersions with different types of polymers, they could increase the availability to around 20% or 40% in rats. That was hugely promising, so that was the path forward that they took.

If you take the 4.7 micrograms and make it into an amorphous dispersion…it goes up to 0.15 milligrams per milliliter, which is a [huge] increase. Fortunately for us, even though it is amorphous, its glass transition temperature is 105°C. The higher the glass transition temperature, the more stable something is and the less likely it is to crystallize at room temperature. That was in our favor.

The initial amorphous formulation that was discovered had a limited tendency to crystallize a bit too rapidly…. We worked on the formulation and came up with a more physically stable formulation that improved exposures dramatically. That basic formulation was what went into the later stage toxicology studies and then into clinical studies and is in the marketed product.

When I first arrived at Vertex, there was an article that was just published in Nature Biotechnology that described some of the CMC challenges. This data came from that article.

The day I joined Vertex in June of 2004 was the first day that telaprevir was dosed in man, so it was really exciting…. One of the first meetings I went to was a meeting to discuss the tox studies, which had been done in July, that used variable exposure, and [the toxicity] was lower than expected. Shortly after that we got data back from one of the Phase I panels where the formulation exposure was zero. They were going up in exposure and getting good exposures, and then one panel was really bad.

It turned out that they had originally done the stability studies on the suspension and showed that it was stable for 24 hours. They had done it one time at room temperature in February. Room temperature in February in Boston, even with a good HVAC system, is different than room temperature in Arkansas in July with a good air conditioning system, and is also different than room temperature at a clinical site in Germany in the middle of a heat wave. Germany rarely has heat waves, so they don’t have great air conditioning.

I think what basically happened that we discovered later was that the basic temperature was too high, so the 24-hour stability wasn’t really 24-hour stability. Of course they dosed at 23 hours and 59 minutes…. We found out all this later. When I got there we did not know what was going on.

The powder that was used to prepare the suspension was amorphous and we characterized it by X-ray – which is how we had characterized it before – and it still looked amorphous. We were not sure what was going on. Were there crystalline seeds in the powder? Was it aging? We were thinking about a lot of different ways to analyze the powder and looking at suspensions and trying to get a handle on why it was crystallizing. We thought about X-ray powder diffraction, solid state NMR, thermally-stimulated current, differential scanning calorimetry and solubility. We did all these things, but we still could not get a handle on it.

In the meanwhile, there was a man named Pat Connelly, who is a physical chemist, and was with Vertex and had left the company, then rejoined Vertex a month after I joined. I met with John Thomson, a very famous character who is in the book The Billion Dollar Molecule, who suggested I meet with Pat Connelly….

I went to a research meeting in San Diego and ended up meeting Pat. We wound up having breakfast together and found out we both live in the town of Harvard, which only has about 6,000 people. We ended up carpooling together



MONTHLY UPDATE - JUNE 2012 quite a bit. There is pretty bad traffic between Cambridge and Harvard so it gave us a lot of time to have really intense discussions about innovation and physical stability problems.

He came up with an idea to use isothermal titration calorimetry, which is used in research to determine drug-protein binding constants. It had never been used for something like this before, but he said, ‘let’s give it a try.’ So we put a little bit of suspension in a vial and plunked it in the machine overnight and came back in the morning.

What we saw was a lovely trace where…if you analyze the stuff at the beginning by a number of methods it was amorphous, and if you analyze it at the end, it was crystalline. We knew exactly what happened and exactly when it happened. This gave us a lot of insight.

We learned that the transition time was about four-and-a-half hours. We always talked about the suspension ‘crashing.’ My mind’s picture was like a snow globe – you turn it upside down and it all crashes. So we learned that it took four-and-a-half hours to crash. It was not an instantaneous event.

We also found that the induction time – how long it takes before it starts this transition – is actually quite variable. Even at a very constant temperature it is quite variable. I think a lot of people know this about crystallization events – that there is some variability about when they happen.

We used this to investigate the problem of what was happening in the clinics and in the tox studies. The induction time – how long it takes for that transition to start – really goes down as you increase the temperature very rapidly. If you are at 40°C it basically happens instantaneously, whereas if you are at 25°C it can take ten hours to start.

Similarly, the rate of transformation – how quickly does the ‘crashing’ happen, whether it is four-and-a-half hours or much shorter – goes up tremendously as you increase the temperature. In terms of a short-term solution on how to get to the next tox study and to the next clinical study, basically we just refrigerated the suspensions. After the suspensions were prepared, we would refrigerate them until it was time to dose, and that improved the physical stability problem.

In the longer term, we wanted to use discrete different formulation prototypes. The preliminary Phase 1 early tox formulation took 12 hours at 37°C to all go to crystalline. So we used a different polymer. In the final commercial formulation, the polymer detection was run out to 72 hours at 37°C and it was still 100% amorphous. This was a huge improvement that led to the PK results I spoke about earlier. By stabilizing it in the body – keeping it amorphous in the body at 37°C – we were able to…get much more drug into the body….

So we had a guy doing research that didn’t have anything to do with pharma development, and me, who didn’t know anything about amorphous stuff up to that point. I vaguely remembered learning something about it in chemistry in school. We got together, had long intense discussions, used a new technique, and it really gave us a huge insight and led us to a really great place.

Understanding Chemical Stability

Once we got the physical stability nailed, we thought we were good. Then we discovered that we had a really bad chemical stability issue, which basically meant that we would have to have a refrigerated product, which is really not very cool. Nobody wanted to have a refrigerated product.

We noticed lot-to-lot differences. So we put it on accelerated stability at 40°C and 75% relative humidity in an open dish. There were huge differences in the rate of degradation lot-to-lot depending on one particular excipient that we were using. We said, ‘gee, what is causing this?’

We investigated every single thing that we could characterize that we could possibly think of. At the end of the day, the answer was fairly simple: the slurry pH of the excipient correlated with stability, and was traced to a residual impurity from the excipient manufacturing process.

We decided we would do studies to try to characterize stability as a function of temperature, moisture and excipient impurity level. We used what are called ‘TRH’ studies, which are useful for all kinds of purposes. We equilibrated the


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samples at different moisture contents and then put them in little foil bags, got all the air out, heat-sealed the bags, and put them at different temperatures. This way we did not have to have a number of different ovens with different temperatures and humidities. We had three ovens at 25°C, 30°C and 40°C, put the samples in, and measured the chemical degradation rates.

We took that data and put it into a huge regression model. The graph showed us, with respect to temperature and time versus different levels of the bad impurity, that with low levels of the impurity the degradation rates were very low. For each one there were three moisture levels – low, medium and high….

Using all that data we could plot contour plots, including the predicted shelf life at each of the conditions and the predicted percent of epimer under ICH conditions. Then we could define the proven acceptable range, or PAR, based on how much epimer we will allow over time.

We defined a normal operating range where we keep the tablet moisture under normal circumstances at less than 2% and the excipient impurity level at less than 100 parts per million, or ppm. That is the normal operating range, which is well within the design space for the proven acceptable range.

With this control strategy you can also predict the stability of packaged tablets by predicting the moisture increase over time. The model was taken from the other experiments that were completely separate from this and used to plot data that was in traditional ICH stability studies.

The end result was excellent stability. It was almost concerning in a way because our registration stability lots had an impurity level of 21 ppm, which is very low. That is good from a stability standpoint, but it was almost bad from a ‘the stability looks too good’ standpoint. But the FDA was very reasonable about it and bought the whole QbD argument and didn’t make us have tighter specs because of the fact that we couldn’t.

We had good collaboration between formulation, analytical and process chemistry, who helped figure out what the degradation mechanisms were from studying the molecule. Materials characterization experts helped with all the different things that we did to characterize the excipient. Technical operations handled the packaging and the controls in the manufacturing. Together they determined the root cause of the instability and developed models to predict stability.

We also worked with the excipient manufacturer and found that if the excipient impurity level was plotted over time that there was an increase. What had happened was that they had allowed their process to kind of drift off in a region where they weren’t washing the excipient at the end quite as well. By instituting a better washing procedure they were able to bring the impurity down again. We set specifications and had the supply chain folks negotiate an ordering spec that was at 100ppm, even though our proven acceptable range was up to 300ppm. In my mind, this all worked together to produce an excellent result.

Advancing the Science of Spray Drying

As I mentioned, this is an amorphous product, and given the high melting point we needed to spray dry it. When we started we did not know much about it, but we learned a lot over the three or four years that we were developing these products. We were thinking about how to use what we learned to do it better next time.

We scaled up the process to a bigger spray dryer. And for other products we want to be able to make stuff early on a smaller scale that will be similar in terms of properties to what we will be making later on the larger scale spray dryer….

During development of Incivek, we developed a huge spray-drying database, with 162 data points on two commercial scale spray dryers – the one that was originally there and the one that was built. They were slightly different models. We did a total of 13 DoEs over three years to generate the database. It was an awful lot of money, time and effort. Some of the stuff that was made was used as clinical material, so it wasn’t all development. It was a huge investment, and we wanted to be sure to make the best possible use of the investment.



MONTHLY UPDATE - JUNE 2012 The end result was that the process is under excellent control with really consistent control of particle size and bulk density. The question was – how do we maximize it and how do we do it better next time?

We now have a collaboration with Bend Research – I am sure many of you in the room do as well. They have published papers and given talks about the concept of using this thing called the ‘HMT ratio’ – the heat and mass transfer ratio. Basically, with spray drying, the faster you dry the droplets the more quickly the solvent comes out, and you make a balloon that is fluffy and hollow, and very compressible….

However, it you dry really slowly it produces balloons that slowly crumple as they dry up, and you get raisin-like particles that are much more dense and are much more compressible.

Bend has defined it in a chemical engineering way – the SDD compressibility is proportional to the heat transfer rate over the mass transfer rate. We can calculate the HMT ratio in terms of what we do in spray drying by using the variables that we have captured.

When I heard about this, I thought that it was fantastic. If we do this and take the data out of each database and calculate the HMT ratio, then maybe we can develop a much better experiment, where by controlling the HMT ratio we can get more orthogonal particles to come out of the spray dryer.

We went ahead and did it, and I agreed to give a talk at the AAPS symposium using the data, expecting that it was going to turn out to be fantastic. What we got wasn’t fantastic. It was a bit of a bummer as I got this data a week before I was supposed to give the talk.

What was supposed to happen, was that when we plotted bulk density versus HMT, we would have a lovely correlation. But it was scattered…. There was an incredible variability in the HMT ratio correlation. There was also some variability between spray dryers.

We tried to figure out why. In talking to Bend, they said that they did it at a constant droplet size. The way that they do their development is they determine the droplet size that they think they want, then they use the HMT ratio to figure out the spray drying conditions. It is much more targeted. What we had done on the spray dryers were factorial DoEs, where we turned the knobs up and down all over the place. So we had different droplet sizes and different everything. Basically, our database was a lot more diverse.

We tried to look at what happened if we chose a subset of data of approximately constant droplet size. It did improve the correlation somewhat when we constrained the data to a narrow range of nozzle orifices and then looked at different feed pressures. But it was still not that great. My take-away from this is that there are still things that we need to understand about how to control these spray dryers and how to collect the data that we haven’t figured out yet. We are working with Bend on how to do this better….

One of the things that I find frustrating about doing a spray drying experiment is that usually if you just do a normal DoE on things like outlet temperature, condenser temperature, low, medium and high, the particle size and the bulk density change together. So if you really want to understand independently what SDD particle size does and what SDD bulk density does, you don’t really get that from this kind of experiment.

What I am hoping – but we haven’t done this yet, so I don’t know if it is going to work – is that if we change droplet size to be small and large, and we change dry rate to be fast and slow, and concentrate on those variables instead of the spray drying variables, that in that case we may be better able to separate out particle size and bulk density from each other. The next time I get a chance to work on it, that is what we are going to try and do.

Scaling Down for New Projects

One of the major reasons we are doing this work with Bend is to try to figure out how to scale down for new projects. Previously, when we did the initial development, we started off on a PSD2 then we went to a PSD1, then we went up to a PSD4. As we changed the scale of the spray dryer we had much more drying time and nozzle changes, and in general the particle size and bulk density increase as you go up in scale.


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Our initial work on a PSD1 showed low particle size and low bulk density, nothing at all like what we got on the FSD and PSD commercial scale spray dryers. We wanted to figure out how to operate the PSD1 in a certain way in order to get the same properties we got on the PSD4.

Bend has a nozzle test [apparatus] that allows them to use a genuine nozzle from a spray dryer and spray it and measure the droplet size pattern. They took some nozzles that we had used on the PSD4 and measured the droplet size as a function of atomization pressure. They figured out what the droplet size most likely was on the spray dryer. Then they figured out what the atomization pressure needed to be to match the droplet size between the PSD4 and the PSD1.

We wanted to keep a constant HMT ratio from what we were using. But then once we have that relationship between the solution flow rate, the feed pressure, and the inlet and outlet temperatures, we have a whole bunch of constraints. So from that, we can figure out where we need to be in terms of atomization pressure and solution feed rate to operate at a particular droplet size and HMT ratio.

We went ahead and did that and used the mobile apparatus that had a six foot extension, which lets us have a longer drying time because we have a longer length of the drying chamber for the droplets. Using the mobile extension and using those scale parameters, we were able to get right in the region we wanted to be in, where we were able to get the kinds of particles on the PSD1 that we had previously gotten on the PSD4 and PSD5. That was pretty exciting for me….

Remaining Opportunities

We are currently scaling up to the PSD5, and we are trying to figure out how to write the regulatory filing to justify the use of some of these parameters so that we don’t have to generate as much data on the PSD5 as we did on the PSD4. We want to be able to leverage a bunch of that information.

One of the big differences between small scale and big scale spray dryers is the density of the plume. There is always one nozzle in a spray dryer. You can imagine that if you have a small scale-spray dryer with one nozzle, the amount of stuff coming out is a lot less than what you have with a large scale spray dryer, which has a much higher throughput resulting in a much denser plume. The heat and mass transfer rates in that plume are going to be different between the large scale and small scale dryers. There are chemical engineering methods that can be used to model heat and mass transfer rates as a function of solvent saturation in the drying gas. We are looking forward to doing that.

When I gave the talk a month ago, I was sitting listening to people who I worked with, yet I still learned things that I didn’t know…. I wondered how it could be that they know things that I don’t know and I know things that they don’t know. We really need to improve the collaboration with people we already work with – sharing knowledge currently residing with different people. We will continue to collaborate internally and externally.

The QbD Filing

A flat line in an EKG is not good. But in a pharmaceutical process that you are running, having a flat line process that is really boring is a good thing. With all the QbD stuff we did with telaprevir, that is basically what we have – a flat line process…. We have produced tons of product with high quality and low variability….

The QbD filing was a little bit ambitious considering this was the first NDA that Vertex had ever written. We did a full QbD NDA…. We had a very complex filing. It was quite difficult for anybody to get their arms around. We started off with a very complicated molecule, which requires a complicated synthesis. It is complicated in every way, from an analytical standpoint, from an API standpoint, and from a formulation standpoint.

We have a very complex manufacturing process. We make API in one place and then we ship it somewhere else, to a different continent, to spray-dry it to make the amorphous stuff. Then we ship it somewhere else to a different continent and we make tablets and film coat them. Then we ship it somewhere else to be put in blister packaging cartons. This is just one supply chain. We have another supply chain and are working on a third one at the moment.



MONTHLY UPDATE - JUNE 2012 Given that we are a virtual company, all this activity is outsourced. So we are dealing with managing CMOs. We have a QbD filing with a very complex molecule, a very complex process, with a bunch of companies involved, and we are implementing QbD at a manufacturer that we don’t control. All of that is very complicated. Working with FDA on this was quite difficult.

We have a very high drug load – a 750mg dose three times a day. Consequently, the SDD [spray dry dispersion] properties have a huge effect on the tablet properties, because the tablet is basically 80% [spray dried material]. We do experiments on this using the spray dryer, but we need to know what the interaction is between those and what happens downstream. To do this, we had to do a DoE of the tablet process to see what happens and how it all interacts.

Trying to explain to FDA what we did with these huge databases became quite difficult. We talked about our design space models. We had models for everything. We had models for dissolution and spray drying control that were multi-dimensional with multiple variables. To make life even more fun, we did not have small little design space squares – we insisted on claiming every corner that we managed to carve out. Trying to explain this to FDA was extremely difficult. For some reason the concept was very hard to get across.

Because we had a square-shaped design space with one corner cut off, we had to represent the specification with an equation – also very challenging to explain to the agency….

To throw in a little more fun, we defined something called ‘allowable model bias [AMB],’ which reflects the uncertainty in the model and allows us to refine it as more process experience is gained.

So if you do these models and have a parameter of 23.15, it is actually, for example, 23.15 plus or minus two. Especially for the spray drying models, if over time you find out as you generate more data that 23.15 wasn’t quite the right answer – it was actually 24.03 – you don’t want to keep using the wrong model to control the spray dryer. You want to be able to refine your models to reflect what you now believe is the truth. FDA is fully in favor of what they call ‘model maintenance,’ but when you actually ask how that is supposed to be done, nobody has a clue. So we came up with the AMB.

We had a lot of trouble explaining this. There was one funny pre-NDA meeting where we were explaining the AMB concept and FDA asked what the reference was for how we defined it. We told them there wasn’t one – we made it up. They looked at us like we were a little bit crazy. So we said that we need to publish it so we can reference ourselves. This is one of the things that I am hoping the IQ consortium can help with – coming up with ways to do model maintenance that everyone can buy into.

[Regarding] the issue with the funny particle size bulk density spec that we had trouble explaining – late one night before an FDA meeting the next day, my son showed me a little animation. I said, ‘let’s take five minutes and see if we can use this to explain it.’ So this is how we did it. If the bulk density is less than some value, then the entire range of particle size is acceptable. But as the bulk density changes, the particle size changes also.

In addition to the models I told you about, we also had a bunch of non-traditional studies, including stability studies – a bunch of work on physical stability predicting relaxation and crystallization rates and other things. On the chemical stability, we did things like an FEI analysis of blister thickness and moisture vapor transmission rates. We used those to estimate shelf life in different packaging.

We did Monte Carlo simulations to estimate combined probabilities. For example, if you have things happening all the way through the process like the chemical stability thing, you want to be able to say that you put all the specs in place and got a certain amount of variability and at the end of the day, you know what to expect. Even though the specification for the epimer is 4.5 based on how we defined the model, there is only one-in-a-billion chance that you will be at 4.5. What you would expect most of the time is 1% epimer, and it has actually moved further to the left since then.

The point of this is to show that it was an incredibly complex NDA. In hindsight, it should have been simpler. We also had a priority review, so it was a six-month review clock, which is a challenge as well.


JUNE 2012 19


Virtual Innovator Vertex Pioneers New QbD Course with CMO Partners

A clear communication pathway with contract partners for escalating issues during and after development has been key to Vertex’ success in building state-of-the-art, quality-by-design (QbD) applications as a virtual company.

Eda Montgomery, who as CMC/QbD quality director helped Vertex develop and gain clearance for two seminal QbD applications over the past year, emphasized the importance of these communication pathways in presentations on the firm’s experience in CMO management at IFPAC’s annual conference in Baltimore in January and again at an ISPE supply chain conference held there in June. Montgomery is now working with Shire to help advance its QbD program.

The two prominent Vertex approvals were for Incivek (telaprevir) in May 2011 – the first drug approved for curing hepatitis C – and Kalydeco – another oral solid, approved in January for treating cystic fibrosis. In a speech delivered in February, FDA Commissioner Hamburg touted Kalydeco as the first drug to “treat the underlying mechanism of the disease rather than the symptoms” (see IPQ “Monthly Update” March 2012, p. 2).

[See pp. 16-26 and 33-37 for more on: ● Vertex’ use of QbD to help address Incivek’s development, formulation, and manufacturing process, and ● the firm’s focus on biopharm modeling and continuous manufacturing to help advance its drug development and QbD efforts in the future.]

The first step in developing a QbD-oriented contract relationship is to put a joint sponsor/CMO project team in place, Montgomery explained. Vertex’ experience indicates

that it is then “crucial to have a process for and an agreement on an open line of communication regarding how to escalate issues, how to manage the relationship, how to talk about what is working well and what needs to be improved.”

The escalation pathway established during the QbD development process, in turn, she pointed out, provides “a nice stepping stone to activities around communication of out-of-specification [OOS] and out-of-trend [OOT] results, conducting investigations, discussions around oversight and how closely managed certain activities are going to be, and finally evaluation metrics and frequency.”

Vertex currently has around 2,000 employees and uses contract partners to do all of its clinical and commercial manufacturing, from bulk production through final packaging.

Montgomery stressed that, with three different CMOs involved in making its marketed products, there are four companies, quality systems and cultures “that have to work well together” for the process to gel. The primary drug substance manufacturer with whom Vertex has been working is Hovione, which has been an important contributor to the overall QbD effort.

QbD Development to Manufacturing Roadmap Established

In her presentation, Montgomery provided a roadmap for the CMO relationship and knowledge management processes needed for a virtual company to take a product from QbD

They approved us on May 23, 2011, which was very nice. It really was an intensive collaboration between Vertex and FDA. There are certain champions of QbD at FDA like Christine Moore and Sharmista Chatterjee who were very encouraging and very supportive. They had many meetings with us and really talked with us a lot to try to help us get through this.

Within Vertex itself, pharmaceutical development – which I am the head of – regulatory, technical operations and quality lived in each other’s pockets for months, answering all of these questions and pulling together last-minute presentations. I think being a small company helped us to be able to do that.

We definitely still need ongoing dialogue. There are many things that we had to pull out of the NDA because we just couldn’t get agreement on the timeline. We are hoping that we can work with those off-line as post-approval changes, and we hope that the IQ consortium can play a role there. So instead of just us giving FDA feedback, we can give them more consolidated feedback from the industry as a whole.

http://www.ipqpubs.com/issues/ipq-monthly-update-march-2012/http://www.ipqpubs.com/issues/ipq-monthly-update-march-2012/


WWW.IPQPUBS.COM JUNE 2012 �0

MONTHLY UPDATE - JUNE 2012development through commercial manufacturing.

Significant landmarks of the journey include: ● defining the contract governance process ● implementing and managing QbD at the CMOs ● managing the knowledge ● putting the knowledge gained to use ● handling the key performance indicators, and ● the ongoing challenges. [Montgomery’s complete analysis of these various components in the Vertex/CMO relationship is provided on pp. 28-32]

The governance process, Montgomery explained, includes a documentation and a quality system piece. Vertex’ approach involved building in the QbD documents to ensure the smooth transition in the transfer from development to commercial manufacturing.

A risk assessment document is another “critical piece to managing the ongoing routine commercial manufacturing as well as managing the changes,” she pointed out.

Overarching these is a control strategy document that explains how the quality systems of the two companies work together on a product-specific basis. And trend reports round out the process.

While its CMO partners may have had limited exposure to manufacturing under QbD, Vertex found them “amazingly receptive to the concept” and they “provided a lot of good input and a lot of good clarification on how we were to do this.”

Non-Conformance and Knowledge Management Need Definition

One of Vertex’ focal points was the non-conformance handling process and how deviations would be defined and dealt with in a QbD context.

To make it manageable for the operators to keep the process in its sweet spot within the traditional manufacturing context, the batch records included the design space for critical and key process parameters with clear manufacturing instructions on how to address excursions.

Another key component of the relationship was defining knowledge management and establishing a coordinated approach to trending key performance indicators and any confirmed OOS deviations, observations and complaints.

Montgomery explained how a coordinated, periodic sharing of results was built in with the suppliers, leading to the shared continuous quality improvement objectives. She also

pointed to the role a “trending protocol” and trending reports play in this communication channel. She went on to provide concrete examples of the improvements in knowledge and process performance that have been gained through this trending program.

In her analysis of the role that tracking of key performance indicators has played in optimizing the CMO processes, Montgomery explained how the QbD investment has paid off in understanding root causes and facilitating working with the CMOS to improve batch records, eliminate human errors through automation and improve equipment performance.

A significant “unintended consequence” for Vertex was to help drive improvements in the batch releas

monthly update - j 2012 · to follow in reviewing it. (see ipq “monthly update” april 2011, p....

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