Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

It’s been a few months since the Obama administration launched the B

, aimed at pooling large collections of data to gain knowledge and insight into everything from national security to the environment to biomedical research.

		Various divisions of the US Department of Health and Human Services are involved in the project, including the National Science Foundation and the National Institutes of Health (NIH), both of which are seeking ways to manage and analyze data collections. As a kickoff to the initiative, NIH placed the human genome project data set into the Amazon cloud for free.

		The CDC has been in the game of sharing data for about two years with its BioSense 2.0 

 and its Special Bacteriology Reference Lab. The Obama initiative brings FDA on board as well with a proposed FDA Virtual Laboratory Environment that will “combine existing resources and capabilities to enable a virtual laboratory data network, advanced analytical and statistical tools and capabilities, crowd sourcing of analytics to predict and promote public health, document management support, tele-presence capability to enable worldwide collaboration, and make any location a virtual laboratory with advanced capabilities in a matter of hours,” according to a White House 

		Last week, Andrew Kasarskis of Mount Sinai’s 

Institute for Genomics and Multiscale Biology

 spoke on NPR about Big Data’s relation to healthcare and medical R&D, such as its potential to help develop better treatment.

		“We try and leverage very, very large-scale data of very, very deep complexity to probe questions about how biology works and that can be used to help patients,” he told 

		For example, Kasarskis and his Mount Sinai team discussed with NPR how data could be used to help understand from the condition of an 18-month old child with a liver condition using data from the baby’s DNA, the parents’ DNA, and from data on liver samples and genetic tie-ins.

		Over the past couple of years, some companies, including GSK, have opened up their compound libraries to global researchers so that existing data can be leveraged to help find new treatments and targets.

		With Big Data surrounding our every move, the possibilities for drug discovery and development seem endless. Has your company used open libraries or data pools? How do you envision Big Data affecting drug discovery and development?

Articles

It’s been a few months since the Obama administration launched the Big Data Research and Development Initiative, aimed at pooling large collections of data to gain knowledge and insight into everything from national security to the environment to biomedical research.

The Potential of Big Data

I'm going into my sixth year working on PharmTech and it's been quite an exciting few years given the changing industry dynamics and major shifts in regulation—both of which are becoming more global and more transparent. It's also an exciting time because 

  anniversary. In fact, you'll find unique retrospectives and forward-looking pieces from industry experts throughout the pages of this issue and on our website, at 

One area of change that I've been following closely is the globalization of the industry. Companies are now expected to perform site visits and audits of all of their suppliers and contact service providers in addition to the multiple audits that they must host from regulators each year. It's been fascinating to watch industry form its own consortiums and third-party auditing schemes to address these needs. The industry is becoming more open to sharing information as well, which is quite a feat in a patent-driven environment.  

At the same time, FDA has taken a much stronger stance during the past few years—and really the agency has had to do this—to manage the complexities of the pharmaceutical supply chain and related challenges, such as counterfeiting and economically motivated adulteration. Our Washington Editor Jill Wechsler had the opportunity to speak with FDA's Deputy Commissioner Deborah Author about these issues and where the agency is headed to meet the ever-expanding needs that come with globalization. See "FDA Adopts New Strategies to Oversee Global Economy", or listen to the full interview as a podcast on 

Industry is also making great strides in the way it approaches manufacturing and testing as it works to implement risk- and quality-based approaches. People are questioning current practice and seeking ways to find and share best practices. We're especially seeing this in the area of impurities and visible particles (see "Atypical Visible Particles"), as well as in continuous processing and platform approaches. In this anniversary issue, we take a look back at how manufacturing, drug delivery and formulation, analytical methods, and outsourcing have changed in terms of key achievements and trends. In addition, experts, including the presidents of PhRMA, BIO, and AAPS (see "Future Innovation"), provide their views on what the future holds for the industry.  

I am happy to say that PharmTech is, and has been, right in the middle of these issues. We are working with the industry and standard-setting organizations to get the best information available to you, whether it's the latest monograph change or FDA-issued guidance, troubleshooting tips for equipment and processing, emerging pipeline and business strategies, or novel approaches to manufacturing. We believe that this magazine offers the most relevant material for the global industry as it carries out day-to-day work, and we intend to continue carrying out that mission. 

Looking ahead to the next 35 years, PharmTech is taking advantage of the industry's transformation and regulatory dynamics to make some changes of its own. Readers and online users are already taking part in our growing online communities through LinkedIn and Twitter (check out the PharmTechGroup feeds). We're also planning to make some visual changes to the magazine in the coming months. Overall, I'm quite excited about what the future has in store and hope to bring you along with us.  

Taking time to appreciate the industry's greatest achievements will inspire growth ahead.

Pharmaceutical Technology: 35 Years and Going Strong

In April 2012, industry experts discussed the issue of atypical visible particles in pharmaceutical raw materials, including excipients, at the joint International Pharmaceutical Excipient Council's  (IPEC) Regulatory Conference and ExcipientFest-Americas Conference in San Juan, Puerto Rico. On the panel were Dr. Lucinda Buhse, director of the Division of Pharmaceutical Analysis in FDA's Office of Pharmaceutical Science at CDER; Ann Van Meter, chair of the IPEC GMP Committee and of the IPEC Atypical Visible Particles Working Group; Dave Schoneker, director of Global Regulatory Affairs at Colorcon and past IPEC–Americas Chairman; and Dale Carter, current chair of IPEC–Americas.  The following pages include an edited excerpt of the transcribed roundtable, which was moderated by 

Editorial Director Angie Drakulich. To listen to the complete and unedited discussion, 

A primary cause of drug recalls during the past year has been the presence of visible particles, that is off-colored particles or black or tan specs, in pharmaceutical products. The presence of visible particles affects both excipients manufacturers and users with regard to standard expectations for mitigating the atypical visible particles and with regard to decision-making about raw material acceptance criteria. The International Pharmaceutical Excipients Council (IPEC) is working to develop and fast-track a guideline on how to measure and properly assess the significance of these visible particles, particularly within white polymer powders. The guideline is meant to dispel any confusion around the presence of particles in excipients and to provide information for excipients users and makers on how to proceed when making decisions about these particles. The following is an edited transcript of a roundtable discussion that took place in April 2012 at the IPEC/ExcipientFest Americas conference in San Juan, Puerto Rico. Featured panelists are listed at left. 

 When elevated temperatures are used with organic substances for drying or solvent removal, these temperatures, even though they're beneficial for solvent removal and reduction of bioburden, can actually char the white powder materials and leave the so-called black specs. Could you comment on this and what other manufacturing or processing techniques may cause these visible particles? 

The Speakers Roundtable session on atypical visible particles at IPEC/ExcipientFest Americas 2012 in San Juan.  

 Probably the most common cause of the particles that everybody sees is charring. There are various points in the process where it's going to get charred and turn a little bit brown or black, and there are various points where there's motion, or compression, that over time will form such particles. It's important to understand that these particles are inherent to the excipient manufacturing process and always will be. There are also errant particles, particles that you don't typically see that show up and probably need a different level of assessment. 

What IPEC really wants to talk about with the industry is zero tolerance (that is, absolutely no visible particles in the excipient material). Zero tolerance should not be the goal because it's unrealistic. What we're trying to do (with the IPEC guideline) is to figure out how to look at the particles that are inherent versus the particles that are not inherent, and how one can come up with procedures and controls to deal with each type. Right now, there is no regulatory guidance on this subject, and everybody is assuming that every particle is atypical—or not inherent—when in fact, they are. This is creating a lot of controversy throughout the industry. 

 To add to that, if you have an abrasive product going through stainless-steel pipes and other things, you're going to scour that product. When you have big crystallizers and large dryers, there is buildup. Even in crystallizations, the color can be just how the crystal formed. It may appear slightly different in color than the next particle. Trying to remove these aesthetically unpleasing specks should not be the industry's main interest. What should be focused on is identifying the reasonable state of art for individual products, following GMP, and separating those occasional off-colored materials from real contamination. 

 Because there are no existing guidelines about how to handle these visible particles, the user's discovery of black specks in raw materials can in many cases lead to an entire batch of material being rejected. Currently, how does one distinguish between the normal specks that may be formed during the manufacturing process and potentially harmful foreign contaminants?  

From an excipient manufacturer point of view, we work very closely with customers to analyze the particles. About 80 to 90% of any particles that I have analyzed that are returned from a customer are off-colored polymer. Unfortunately, when you're dealing with pure white powders, it is common to have these very, very small dark particles, and even though they're very small in number, they do stand out. I understand that they cause alarm; but again, 90% of them are purely the listed polymer. 

 From an excipient user perspective, we've learned that most companies don't talk to their suppliers about these particles. Instead, all kinds of analyses are done to prove that a charred particle is something it's not. Users then have tons of data and still don't know what to do about the particles and they end up rejecting the batch.  

The supplier, however, could probably explain why the particles are there, what they are, and how they control them. For example, a supplier might say, 'If the particles are brown, that's normal and you probably don't have to do a whole lot of analyses unless you have some reason to think it's something else. If the specks are purple, however, you need to go to the next step in analysis.' The missing link here is communication. 

 When such a batch rejection occurs based on atypical visible particles, that decision affects not only cost but also the supply chain, and potentially can lead to a drug shortage. What are your thoughts on this?  

 Yes, very few particles can cause the rejection of an entire batch of materials. But I'd like to clarify that when we're talking about these particles, we're not talking about something that is pervasive or gross, we're talking about just a very, very few micron-size particles in an entire batch of material. At a customer location, if those are seen at receipt, then the entire batch could be quarantined and shipped back. As an excipient manufacturer, that rejection incurs tremendous cost because the material has already been manufactured and shipped. Then you have to bring the material back and perform an appropriate disposition; there's often no rational thought as to why the material was rejected. Sometimes, the recipient decision is just visual— 'I see black specks; I can't accept this lot.' The alternative is for the user to take a controlled approach to call the material manufacturer, do the appropriate investigation, and release the material. 

 FDA does not have an official position on this subject yet, but are there any visible particles that are considered acceptable in raw  materials today or should everything be ruled out? 

As an agency, we want to know that you understand what product you're making, so that you know what is or isn't acceptable.... There are risk-based, science-based decisions that you need to make as the manufacturer of the final drug about what you can tolerate in your incoming raw materials, including the excipients. So if you have particles, we would look to see that you understand what they are. Perhaps it's as simple as having a discussion with your supplier and being able to explain to the agency what the particles are and why they are not a risk to public safety or patient safety, which is our prime concern. Risk management, good science, and always keeping the safety of the patient in mind is what we're looking for. 

 In the food industry, there's a guideline on acceptable filth that specifically states how many insect parts are okay, how many wings are okay, and how much dirt can be present. Now we don't necessarily want to go there in the pharma industry, but, again, the concept that FDA can't find a particle to be acceptable is not true. FDA on the food side has been saying that for decades, and a certain amount of particles, if you will, is the reality. We just need to figure out for our industry what we can do in a reasonable way.  

 Can you provide some insight into the pending IPEC guideline on atypical visible particles in excipients and its goals? 

: We have a subteam in which excipient manufacturers are looking at what a responsible manufacturer in full GMP compliance would need to do to provide a high degree of assurance to customers (excipient users). The manufacturer needs to be able to tell the customer that it has the issue under control, that it has minimized the particle occurrence to the greatest extent possible, and that it can communicate with them about this topic. 

The next phase of our plan is the user phase. Users will need to have a subteam where they look at issues such as, 'What do we do upon receipt? If we see a black particle, do we automatically reject?' And in some cases, users will need to re-examine their decision-making procedures in this regard.  

Ultimately, we hope to bring together the responsible manufacturing point of view from the maker's side and the responsible acceptance procedures on the user's side, all with the focus on patient safety. Once we have what we consider a good guideline, we hope to sit down with FDA and review it with them to gain acceptance and move forward. 

 To be clear, from the point of the IPEC Executive Committee, this guideline is not meant to give manufacturers the ability to avoid high quality standards. If you have a belt that is shearing pieces into the product—the resulting specks are not inherent. That problem needs to be fixed and GMP practice must apply. 

 The IPEC guideline may suggest taking a customer complaint about specks being found in excipient materials and using that complaint to perform a risk assessment. Can you provide some more detail on what's planned? 

 The way that we think a good manufacturer should behave in this regard is that you need both a feed-forward and a feed-back risk assessment. The feed-forward risk assessment involves having documentation of the process that details where these types of particles may be formed. Then a company can perform a review or a mitigation when they are found. We also want a feed-back risk assessment, which means that when a manufacturer gets a customer complaint, you can take the particles, analyze them, and look back in the manufacturing process to see where the particle may have been generated. That risk assessment should then be updated as necessary.  

In addition, I'd like to make a comment about testing and how we can learn how to mitigate some of these issues. We get asked all the time about whether our sample plan covers visible particles. The answer is, you sample, and you evaluate your samples for particles of any kind that would be atypical. However, when you're looking at a performance level, even if you're generating off-color particles, in many cases, you're looking at performance levels of 6, 7, 9 Sigma, and beyond. So anything that you can grab a sample of, you can ensure yourself that if you have an off-color particle that may end up in a final product, you're going to catch it. 

From FDA's perspective, what is your take on the IPEC approach discussed so far? 

 This is a conversation that's going back and forth between manufacturers of excipients and the users of the excipients because perhaps the communication has not been there between those two groups, and I think this guideline will really help move that communication forward so people understand the excipients that they're using and then can use the good science they need to decide what to do moving forward.  

And then they can have a better understanding of what 'out of normal' is because, obviously, if an excipient does come in and you are used to 2 particles in 200,000 kilos and one day it comes in as 10 particles out of 200,000 kilos, that raises a red flag. You need to have the ability to call your supplier and talk about it. And maybe they already know that the particles are there, or maybe it's something completely different, and you both need to go back and do a complete CAPA and take a look at perhaps that pipe that needs to be replaced because it's 25 years old, and so forth. And if you aren't communicating, then perhaps some material could get into the market that maybe should have been stopped had there been better communication. 

Overall, it's a good place for both the suppliers and the users to start talking and figuring out what they want to put in this guideline. As an agency, we're happy to take a look at the guideline when a good draft exists and see what we think.  

There is clearly frustration on both sides, user and maker, with this issue. What types of dialogue do you think need to happen beyond what's already taking place? 

 There's got to be an understanding of how products are made, their capabilities, and how they are used. The makers of excipients have concerns over their own intellectual property. In making excipients, you don't typically, for equipment or certain processes, patent them. This confidentiality is what gives a certain company an ability to make a certain product of a certain quality. But companies have to get beyond this frame of mind in order to talk about sources. They have to build a quality partnership. This dialogue, however, needs to start in the development process when companies are choosing excipients. Early conversations are key. 

 Having this guidance in place will provide the safe environment that not only says it's okay for these particles to exist, but that also encourages makers and users to talk about this issue because, as we have has alluded to, it's been there all along. When you have these discussions, not only do you build a much higher degree of trust, supplier to maker, but you also avoid panic.  

 [These ideas about dialogue] support a lot of the initiatives that the agency has been pushing, such as quality by design and understanding better how raw materials affect the final product. So it can only help to be having that communication between manufacturers and users and being able to understand the variability in your raw material and how then you can make sure that that variability in your raw material can be taken care of in your own manufacturing process so that the end product is potentially less variable or at least will no longer have a high probability of being rejected down the road. 

"Your write up on the visible particles conference was very useful, particularly hearing FDA's perspective.  I also liked D. Schoneker's comment on FDA's acceptable level of particles (and filth) in food.  It's extremely helpful that FDA says unequivocally that these particles don't present a health risk.  Similarly, most particulates in drugs, particularly oral ones, don't present a health risk, they present a quality issue. From my experience, atypical matter from supplier excipients is less common than atypical matter that occurs during manufacturing.  The latter are usually associated with manufacturing equipment or items, e.g., a piece of teflon or other polymer, particle of stainless steel, etc.  The materials are usually present an extremely low hazard and don't present a risk to patients (I'm a toxicologist by training).  However, we still must do toxicology assessments of each. The issue with the JNJ plant in Fort Washington also included this kind of particulate matter.  Hence, it's a general challenge within industry." --Dave, Large Pharma Company, US

An industry roundtable on how users and makers can best assess and manage black specks.

Atypical Visible Particles

 Christie Bloomquist is a partner in health practice at Hogan Lovells, a global legal practice firm based in Washington DC.

	I’ll admit it, I had trouble sleeping this week, knowing that we’d finally know what the Supreme Court thought about the Constitutionality of key Affordable Care Act (ACA) provisions.  Mostly, I wondered if the law that I had spent the last few years of my life working on during its debate in Congress and throughout implementation would be the same at the end of the day as it was at the beginning and what this would mean for the pharmaceutical industry.  Call me nerdy, but I suspect that I wasn’t alone in my tossing and turning all week.

	And now that the speculation is over, what’s clear is that the Supreme Court’s decision means status quo for the industry.  Pharmaceutical manufacturers will continue to do what they’ve been doing for over 2 years – implementing ACA.  They’ll continue to process discounts in the Part D coverage gap, they’ll continue to work through the expansion of the Medicaid drug rebate program, they’ll continue to pay the industry excise fee, they’ll continue to think ahead to the implementation of a pathway for biosimilars – and, most importantly, they’ll continue to do all of these things while pursuing innovation of life-improving medicines.

	I suspect that today’s ruling will also feel a bit like hitting the fast forward button.  For several months, implementation of ACA has been mired in the will it or won’t it debate, slowing down implementation efforts aimed at establishing state exchanges and the like.  Now, with everyone realizing that a lot of work needs to be done in relatively short order, the pharmaceutical industry will spend significant time on ensuring appropriate coverage and access to their products.  These are issues that will require a deep understanding of a complex law with interrelated provisions.   After all, there is a reason why ACA didn’t include a severability clause.  In addition, the industry will continue to parse through the Supreme Court’s decision on the Medicaid expansion to determine any potential impact.

	Separately, with the Supreme Court’s decision now officially behind us, the countdown to the next big event – the November elections – will commence.  The industry will continue to look for policymakers in Congress that value the work industry does.  And, while it won’t change the pace of ACA implementation, the November elections will continue the speculation on the fate of the law and future legislative efforts.  All of these activities will take place at the same time as an even bigger countdown clock continues to wind down, the clock for reconsideration of deficit reduction measures, likely at the beginning of 2013.  The pharmaceutical industry is acutely aware of potential pay-for measures having lived through the rise and fall of the Super Committee and calls for the industry to provide even deeper discounts in federal health care programs.  They will continue to be aware that navigating those issues requires expertise and sharp attention to detail.  Given those realities, more sleepless nights certainly lay ahead.

This guest blog was written by Christie Bloomquist is a partner in health practice at Hogan Lovells, a global legal practice firm based in Washington DC.

Healthcare Reform and Next Battles for Industry

Here in Boston, the crowds are bustling at the BIO 2012 Convention and Exhibition. Today, BIO unveiled survey results that polled about 170 biotech industry leaders and 800 US voters, conducted by Hart Research and Public Opinion Strategies. Approximately 63% of biotech industry leaders said that they feel “very optimistic” about the future of biotech and its ability to develop new products that will meet global needs. A similar survey was conducted in 2007 showing that 79% of industry leaders were optimistic about biotech’s future. So there is a dip in optimism here, but considering the economic downturn of the past couple of years, such a change is not surprising.

		Among major challenges the biotech industry is facing, the top two listed concerns were regulatory burdens and lack of available capital. A close third was tax concerns. Investors in all industries have been avoiding risk more than they have in the past, and in biotech, seem to be straying away from early stage investments. One interesting connection here is that more than half of the BIO polled participants say their company has been approached by a foreign government to move operations overseas. Tax policies and incentives have a large role in this development–companies in many cases are finding more appealing situations outside of the home base.

		BIO’s survey of American voters tried to get at this issue–at least from the perspective of US companies being tempted to move business abroad. They found that 56% of voters support the enactment of US tax policies and direct funds for biotech businesses. Whether or not the government picks up on this notion remains to be seen, but survey respondents did note that “partisan gridlock”in Washington is a chief concern in terms of the how the industry evolves over the next 5 to 10 years. The survey noted that since 2002, Americans have largely been favorable of the biotech industry (ranging from 44 to 49%) but what’s interesting is that those stats are largely based on voters who don’t know much about what the biotech industry does. When pollers explained what the industry is about, that percentage shot up to 83% being favorable.

Here in Boston, the crowds are bustling at the BIO 2012 Convention and Exhibition. Today, BIO unveiled survey results that polled about 170 biotech industry leaders and 800 US voters, conducted by Hart Research and Public Opinion Strategies.

LIVE from BIO 2012: Capital and Tax Policies Burden Biotech, but Optimism Remains

The revised US Pharmacopeia revised chapters on elemental impurity limits and procedures (<232> and <233>) are set to become official by the end of the year, and companies are beginning to think about implementation, which will be required by May 2014 (see back 

 from the USP website, the new chapters will be published in the Second Supplement to USP 35–NF 30 (official Dec. 1, 2012). Conformance with these chapters will be required by May 1, 2014. In the interim, all references to USP General Chapter <231> Heavy Metals will be removed from monographs in the compendia.

		The International Conference on Harmonization (ICH) Working Group on Elemental Impurities is simultaneously working to develop a harmonized approach for controlling these impurities, including risk-assessment recommendations and safety limits for specific metals, that meet testing and regulatory filing requirements at the global level. USP has noted that its expert panel is not waiting for the final recommendations from the ICH Q3D Expert Working Group but does note that the limits in the new General Chapter <232>, except for mercury, are in line with those in the stage 2 draft of the Q3D 

. “At a future date, the Expert Panel intends to revisit General Chapter <232> relative to the Step 4 outcome of ICH Q3D deliberations,” says the USP elemental impurities webpage.

		PharmTech is hosting and moderating a free educational 

 about the revised USP chapters on June 14, 2012, with a specific focus on new testing procedures and practices for detecting elemental impurities. Instrumentation, key challenges, best practices, and will be addressed.

The revised US Pharmacopeia revised chapters on elemental impurity limits and procedures ( and ) are set to become official by the end of the year, and companies are beginning to think about implementation, which will be required by May 2014 (see back story).