Whodunit: NIR and Why Melamine May Be Poisoning the Pets

Analytical instrumentation really does help solve a number of mysteries.

One subject that’s apparently being discussed in some near infrared (NIR) spectroscopy chat rooms (places where I do not dare to tread) is NIR, gluten and wheat. An expert source informs me that melamine polymers can “fool” NIR devices into recording a higher level of protein in wheat.  Melamine monomer is toxic…and is believed to be behind the recent gluten poisonings and pet deaths from tainted cat and dog food.  Which raises the issue:  was melamine added knowingly, by those selling the grain, or by another agent further down the distribution chain?

Apparently, the expert says, this has happened for years. “Farmers used to hose down the wheat because they were paid by the ton. NIR was used because a Kleldahl nitrogen was done for the protein (can also be fooled by melamine which is 2/3 nitrogen by weight) and Karl Fischer was done for water. Both are time-consuming analytical processes. One NIR can do both in seconds…in fact, since the later 1970s, early 1980s, all grain sold overseas was shipped from the US after being analyzed by NIR. Unfortunately, the C=N-N-H of melamine is close enough to protein amides to fool the simple filter instruments used. “

 The pharma distribution chain is also open to adulteration risks, and stories like this are playing out every day, all over the world, only we can’t yet assess the size of the problem. It’s technologies like NIR that will help keep supply chains safe.

AMS

Papers Requested for the Winter Plasma Spectrochemistry Conference

For the hard-core analytical geek, we’ve received a call for papers to the 2008 Winter Plasma Spectrochemistry conference in Temecula, California, from January 6-12.

Topics include: elemental speciation, laser asisted spectroscopy, new plasma insrumentation, micronebulizers and plasmas and stable isotope analyzers. To submit an abstract, email wc2006@chem.umass.edu

For more information, see the brochure, Plasma Spectrochemistry Conference

Mechanical Calibration Gets the Nod for Dissolution Testing

Dissolution testing is extremely important to drug safety, but it is still somewhat imprecise and has become an area of controversy, but an inside source says that mechanical calibration (which had been questioned by industry traditionalists and by USP, which  viewed it as supplemental to, rather than a replacement for, existing methods) will soon be listed as an “industry consensus” method for validating dissolution testing equipment. Here, the relevant “working standard” that ASTM’s E-55 committee has been developing.

For links (some of which work) to recent and relevant articles, including a summary of dissolution science, check out this recent newsletter from Varian. Varian Dissolution update. Those of you who have subscriptions to Science Direct should have no difficulty retrieving full text.

Janet Woodcock’s Testimony on Follow-on Biologics; A Lab Scientist’s Toolkit

FDA’s CMO Janet Woodcock testified at the House of Representatives committee hearing, chaired by Representative Waxman, today, in a thorough presentation of the issues and nuances involved. Testimony at House Committee Hearing today.

An excerpt below

“Current technologies, such as peptide mapping, protein sequencing, and mass spectroscopy enable manufacturers to determine, with certainty, the amino acid sequence of a recombinant protein. However, the amino acid sequence is the most rudimentary characteristic of a protein. Conclusive analysis of other aspects of a protein’s structure requires much more sophisticated technologies and is fraught with uncertainties that are proportional to the size and complexity of the protein itself. Such complexities include: folding of the protein’s amino acid chain into highly organized structures, post-translational modification of the protein with a broad range of biochemical additions (e.g., glycosylation, acetylation, phosphorylation, etc.), and association of multiple protein molecules into aggregates. It is the combination of the protein’s amino acid sequence and its structural modifications that give a protein its unique functional characteristics. Therefore, the ability to predict the clinical comparability of two products depends on our understanding of the relationship between the structural characteristics of the protein and its function, as well as on our ability to demonstrate structural similarity between the follow-on protein and the reference product. Although this may be currently possible for some relatively simple protein products, technology is not yet sufficiently advanced to allow this type of comparison for more complex protein products.  Functional characterization, using in-vitro tests, is also of great importance in assessing the similarity of two proteins. For proteins with a well-understood mechanism of action and available functional assays, extensive functional comparisons will enhance understanding of comparability. Future scientific advances may facilitate the ability to perform more meaningful functional testing…

We asked BMS Senior Scientist Declan Moran who is working as part of a multidisciplinary research team in Ireland to develop new bioanalytical tools and methods, which existing commercial analytical technologies (besides the ubiquitous “MALDITOF” were becoming more important in helping to evaluate comparability of “followon” and original biogenerics, and he shared the following insights.

“…No single analytical method can be used to definitively assign comparibility. Orthogonal approaches are proving very useful, and “hyphenated MS solutions” offer 85-90% of the answers, although NMR would still be needed to confirm configuration. Recent advances in gene expression technologies will play a crucial role, since most biotherapeutics are hosted in parent cells(CHO being the favorite due to past FDA approvals), so separation of host cellular material from protein of interest is key and the presence of such things at mitochondrial DNA or RNA could be significant.

Array recognition technology is also becoming very effective in addressing issues, whether these are SPR based technologies such as Biacore or Lectin arrays, as patented by Procognia. All serve to build a fingerprint of the therapeutic of interest.

There is no getting away from traditional wet techniques sucha as IEF and SDS -PAGE as these are still best at separating isoforms.

But here is the rub. To truly say a follow on Biologic is the same as the original, the isoform fingerprint will have to be identical. Thus sensitivity now plays a key role. As yet no analytical methods can successfully map a full isoform sequence and therefore the isoform with the best half life and most bio availability may in reality only represent a very small proportion of the pattern in percentage mass terms. However if the FDA adopts a risk mitigation approach and determines the success of a follow on based upon its treatment affect and lack of immunogenicity than all is up for debate as they will be looking at patient response as the measure and not absolute comparibility.

If follow ons are allowed in the manner stated above then the big players will need to look very seriously into their R&D expenditure, as the cost to market will not support a challenge in the initial years of return on investment.

The key analytical methods shaping up in this area are:

MS- TOF,Q-TOF 3Q all with hyphenated capabilities

Array sequencing(SPR Lectin Ab specific)

qPCR

IEF SDS-PAGE

Any platform based around signal enhancement and sensitivity (whether optical or acoustinc); fluorescence is becoming a key indicator…”

ASTM’s E-55 Committee Approves First Process on Pharma Process Design

This is important news for those interested in process analytical technologies (PAT).  Only now,  the “news” is two months old. No news release sent out. Typical.

ASTM International Process Analytical Technology Committee Approves First Practice

ASTM International Committee E55 on Pharmaceutical Application of Process Analytical Technology has now approved its first practice. ASTM E 2474, Practice for Pharmaceutical Process Design Utilizing Processing Analytical Technology, is under the jurisdiction of Subcommittee E55.02 on PAT System Implementation and Practice.
 
Practice E 2474 covers process design, which is integral to process development as well as post-development process organization. In the context of ASTM E 2474, process design refers both to the activities involved in designing a process and the outcome of the activity. E 2474 describes practices that should be considered in order to design effective and efficient pharmaceutical manufacturing processes that ensure product quality and performance.
 
Gerd Fischer, member of Committee E55 and director, industrial quality and compliance, Sanofi-Aventis, says that the Process Analytical Technology guidance published by the U.S. Food and Drug Administration in 2004 introduces PAT as a regulatory framework that will encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing and quality assurance. ASTM E 2474 outlines scientific principles and tools that support process design in a PAT environment, and that are suitable to facilitate innovation and risk-based decisions.
 
“E 2474 will help to focus process design and development on science- and risk-based design strategies to manage variation,” says Fischer. “Integration of PAT principles and tools during process design will enhance opportunities to build, maintain and expand science- and risk-based process understanding throughout a product’s life cycle.”
 
Because process design is such an important part of the development process, as well as post-development process optimization, Fischer notes that the main users of E 2474 will be pharmaceutical process developers, manufacturers and quality assurance workers.
 
ASTM International standards are available from Customer Service (phone: 610/832-9585; service@astm.org) or at www.astm.org.

More Collaboration Needed On Excipient Selection and Development, IPEC Says; Excipient Master Files Would Advance This Cause in Europe

The wrong choice of excipient has led to delays or failures for many new drug candidates. A position brief from IPEC, which recently held a seminar on this subject, notes the need for

• Strong communication channels between suppliers and the pharmaceutical industry are pivotal for the development of innovative excipients that enhance drug efficacy and streamline manufacturing operations
• Close collaboration,  to ensure that regulators take on board the concerns of all those involved in the use of excipients.  

Below, verbatim, is IPEC’s summary of some highlights from its recent seminar.

Carl Mroz, Chair of IPEC’s European Regulatory Affairs Committee advised companies on how to expand their excipient business in markets such as China and Russia. He pointed out that Japan recently amended its 1948 Pharmaceutical Affairs Law to allow for the filing of an Excipient Master File (EMF) and that European stakeholders should focus on doing this in Europe as well.

Mroz said: “We want a mechanism that allows novel excipients to come faster to market in Europe. Without new excipients you are stifling innovation and there are many good ideas which never get off the drawing board because there is no system to introduce new excipients within Europe.”

The EMF model is already in place in Japan and in the USA, and it is imperative that Europe catches up, added Mroz.

“If you are interested in a new drug delivery system that involves a new excipient, there is no impetus to invest in that sort of R&D at the moment because the regulatory hurdles are so high. If a DMF system were in place holding all confidential information safely, eliminating the need to submit sensitive data to every single potential customer to assess multiple times, the boost to the advancement of technology would be enormous.”

Both patient need and process capability must guide excipient selection, seminar delegates said. However, as new legal requirements for Good Manufacturing Practice (GMP) in the production of certain excipients are introduced in Europe, suppliers will be required to offer excipients made to the similar GMP principles as active pharmaceutical ingredients (APIs).
 
To assess the impact of applying GMP regulations on excipients, Dr Rui Santos-Ivo, Enterprise and Industry Directorate-General at the European Commission,  attended the IPEC Seminar and invited all stakeholders to take part in a public consultation and announced the launch of a questionnaire on the directorate’s website.
 
Dr Santos-Ivo said: “We need high safety standards to promote patient safety and that is why we have identified some categories of excipients where legislation is required. Nevertheless, we also believe that adequate regulation is a tool for improving the competitiveness of companies, not only in Europe but worldwide.”
 
“We must also avoid placing unnecessary burdens on those affected by the new directive, without of course compromising patient safety. For me it is very clear that IPEC has ample knowledge in the field so it is very important that those who work directly with excipients offer their expert views in the consultation.”
 
IPEC has already made a significant contribution to the debate by publishing a GMP guide for excipients, a practical authoritative document that not only helps excipient suppliers meet the increasingly stringent demands of the pharmaceutical industry, but also makes it easier for pharmaceutical companies to ensure their suppliers are meeting acceptable quality levels.
 
Impurities
 
Excipient suppliers are also faced with new rules on the acceptable limits for
genotoxic impurities in pharmaceuticals. Although new guidance from the European Medicines Agency (EMEA) that came into force on 1 January 2007 does not refer specifically to excipients, the regulator is expected to take into account the toxicological assessment of genotoxic impurities in excipients before granting marketing approval for new drugs.
 
This poses a great challenge for excipient suppliers because routine synthesis is not possible without the use of reactive materials which are potentially genotoxic, making the presence of genotoxic impurities in excipients inevitable in some cases.
 
Dr Peter Kasper, rapporteur for preparing the EU Guideline on the Limits of Genotoxic Impurities, told the IPEC seminar: “A considerable proportion of all synthesis products in pharmaceuticals potentially contain genotoxic impurities, so this is certainly a major regulatory issue. Whether this poses a health risk is another question, because we are talking about very low levels and it is very difficult to quantify the risk.”
 
“Our guidelines help provide some much needed clarity to the assessment of genotoxic impurities. If companies are aware of this problem from the very start, most have the knowledge and the expertise to deal with it, so I don’t think these new guidelines will have a negative financial impact.”
 
According to the guidelines, published by the EMEA’s Committee For Medicinal Products For Human Use (CHMP), a threshold of toxicological concern (TTC) of 1.5 µg/day intake is considered acceptable for genotoxic impurities without sufficient evidence for a threshold-related mechanism. Higher limits may be justified under certain conditions, such as short-term exposure periods.
 
Variability
 
It is often assumed that such demands for regulatory compliance will inevitably lead to less variability in the excipients used.  But Janeen Skutnik, Director Technical Affairs at Pfizer and Chair-elect of IPEC-Americas, challenged the view that as pharmaceutical manufacturers in Europe concentrate on International Conference on Harmonisation (ICH) concepts, such as Design Space and Quality by Design, they will tighten their excipient specifications.
 
Skutnik said: “A lot of pharmaceutical companies are having discussions with their procurement teams to help them understand the impact of these guidances and urge them to embrace scientific and risk-based discussion with excipient suppliers.”
 
At the moment there is a lot of wastage in pharmaceutical manufacturing as the industry has not been continually improving and understanding process parameters, with the result that waste can be as high as 50% for some products, while factory usage rates can be as low as 15%. In most pharmaceutical companies manufacturing spending constitutes 25% of expenses which is equal to R&D investment.
 
“Pharmaceutical manufacturing produces products of reasonable quality, but at great effort and cost,” according to Skutnik. “Through increased formulation understanding and efficient knowledge transfer, we can implement ICH Q8 Q9 and Q10 while bringing in new excipients that achieve better results for our processes and more effective medicines for our patients.”
 
More extensive knowledge of critical product and process parameters and quality attributes should lead to more innovative use of excipients, yielding financial savings and better medicines, she said.
 

-AMS

Nancy Mathis Takes on PAT’s “Chicken and Egg” Problem

One problem with process analytical technologies’ (PAT) acceptance in pharma is the fact that companies are unwilling to invest in PAT until they know that it will work for them.  And knowing it will work generally requires investing in technologies and hiring consultants to help with methodologies, and trying PAT out. As a result, many companies are waiting to see what their competitors and others in the industry do first.

Nancy Mathis, founder and CEO of Mathis Instruments, whose thermal effusivity analytical technology has found growing acceptance in pharma, is now establishing a consulting company, Mathis Solutions. The move parallels the overall move within the industry to de-emphasize the “analytics” and “technologies” of PAT to focus on “process.”

“My Ph.D. got the better of me,” she says.  “I wanted to spend more time as a scientist helping clients understand their PAT data.”  The company will offer PAT profiling with multiple technologies at the same time.

Below, an excerpt from today’s press release announcement…

…The new company will be focused on assisting clients in capturing the value of process understanding to serve clients who want to access the value in analytical techniques and interpretation without incurring large upfront expenditure on capital equipment and expertise.

A typical situation is a pharmaceutical or generic client who is struggling to achieve a robust powder manufacturing process. Until the source of the problem is understood, the client does not want or need to purchase an instrument, but simply needs flexibility in how they structure their initial PAT efforts. “The services offered by Mathis Solutions focus on helping pharmaceutical companies use the appropriate level of analytical technology to maximize the value”, comments Dr. Nancy Mathis, the firm’s President.

Mathis Solutions brings together the tools and expertise to assess the problem, make recommendations and oversee the implementation of solutions. The solutions can be as simple as a change in an excipient
specification or as far reaching as automation supported by on-line analytical techniques.

This move will focus on the knowledge, not the tool. “My love has always been the use of analytical technology to provide insight into material properties”, says Dr. Mathis. Mathis Solutions will put understandable process information into the hands of their clients so that informed low-risk decisions can be made about the next step in the product life-cycle.

Extra process information is an invaluable component on the road to robustness, especially during, the production of registration batches or clinical supplies and during product transfers or scale-up.

“Mathis Solutions ends a ‘chicken-and-egg’ problem“, states Mathis. “Clients are cautious about spending money on a tool until they know it will work. Until now, they can’t know it will work without buying it first. “
 

Stephen Closs, Manager, Pharmaceutics and Process Technology at Patheon agrees. “We really wanted to profile our client’s blend to better understand the chemical and physical uniformity profile of the process. We proposed NIR and effusivity data”, stated Closs. “Mathis Solutions is unique in that they give us the ability to access technologies on a short-term basis to assist our clients, avoiding the need for major or longer-term capital commitments. They are the Navy Seals of PAT!”

Dr. Nancy Mathis, is a thought leader in the application of PAT tools within the pharmaceutical industry She is a founding member of ASTM E55 on Pharmaceutical Manufacturing and the author of the USP chapter <1073> on effusivity. She has led or collaborated on over 100 projects to improve process understanding.

Biogenerics, The Wall Street Journal, and the Big, Grey MALDITOF

The Wall Street Journal’s excellent article on biogenerics (subscription only, unfortunately) yesterday, coauthored by Leila Abboud (of “Three-Story Blender” fame, whose 2004 article first brought drug manufacturing issues to the attention of the U.S. public)  described a visit to Pliva’s laboratories in Croatia to interview chemist chemist Marko Velutic, whose job it is to see how generic versions of EPO match up against originals.

Toward the end of the article, mention is made of  mass spectrometry and “a big gray machine dubbed the Maldi Tof” that sits in the center of the lab.  Although the article makes it sound like a Croatian nickname,  what that  stands for is “Matrix-assisted laser desportion/ionization” and “Time of Flight” mass spectrometer.

Which points to the dizzying pace at which new changes are taking place in analytics and different technologies being combined.  The acronyms gave me and some of my colleagues a headache at Pittcon recently, but we will attempt to demystify them in April’s issue, in reports on follow on biogenerics, new bioanalytical techniques that are being used to analyze them and their limits.  Stay tuned.

Sandoz’ Ajaz Hussain and J&J’s Jay Siegel Testify at Biogenerics Hearing

The Orange Book blog ran a nice summary of this, but to watch a videotape of yesterday’s Enzi-Kennedy Senate Committee hearing, click here.  (It starts at 17:25…before that, you will hear clanging coffee cups and rustling papers).  Among the experts testifying was Novartis/Sandoz VP, Dr. Ajaz Hussain, formerly deputy director of the Office of Pharmaceutical Sciences at CDER (and known in very different circles as the “father of process analytical technologies (PAT)”)

Amazing that these videos and transcripts are available so soon. (Video quality is another thing, though….just keep the screen size small to avoid the funhouse mirror effect)

Among the key issues:  would full clinical trials be required, or would more limited studies (e.g. pharmacokinetics) suffice?

Read  Ajaz Hussain’s testimony on Followon Biologics, J&J’s Siegel ’s J&J’s Siegel testimony at biosimilars committee meeting and the EC’s Dr. Nicholas Rossignol’s testimony here.

The video’s a bit like Grade B C-Span, but the personalities of the senators and speakers still come through.  Senator Enzi, for instance, uses endearingly homespun similes to contrast generic small molecule drugs with biogenerics, with a regular generic being like a “starter house” and a biogeneric, like a “skyscraper.” 

-AMS

More from Pittcon: Bioanalytics a Key Focus

There are few things more dull than reading any “show roundup” (except, occasionally, having to write one), but there were some extremely significant technologies introduced at Pittcon 2007, including some that may prove useful one day in helping sort out issues with the biogenerics and followon biologics that everyone is talking about. Here are just a few (for information on others, see www.pharmamanufacturing.com). So, for those whose eyes do not glaze over when flooded with acronyms, here is a mercifully brief summary

Waters won the Gold Editor’s Prize this year, but Silver and Bronze were both “ties.”

Tied for Silver were ThermoFisher Scientific and Paraytec.  ThermoFisher Scientific’s LTQ ETD marries electron transfer dissociation (ETD)*, a technology developed at the University of Virginia, and Linear Ion Trap Mass Spectrometry. It is now being used by researchers at the Max Planck Institute for Biochemistry, and elsewhere, for large-scale analysis of protein function. 

Paraytec’s ActiPix capillary-based UV absorbance detectors and spectrophotometers use a patented technology to extend the use of UV Vis. The instrument uses UV for both quantification and sizing. According to chief science officer David Goodall, this instrument allows scientists to see a complex reaction taking place in real-time, while quantifying the components.

Tied for Bronze were Bruker, for its laptop computer-sized FT-IR system, as well as Horiba Jobin Yvon’s Activa  ICP-MS (inductively coupled plasma mass spectrometer) using charged-couple device technology. ICP-MS is a rapid, sensitive way to determine selements’ presence within solutions at less than 1 ppb.  (For more information, click here. http://www.jobinyvon.co.uk/ukdivisions/emission/activa.htm )  

*And now, here’s more on ETD, which has been a strategic technology acquisition for ThermoFisher. An ion fragmentation technology, it is said to offer protein sequence information that can’t be obtained from the conventional methods now used on ion trap mass spectrometers.  ETQ has already been used with the LTQ for biopharma applications such as mapping posttranslational modification sites, particularly phosphorylation.  It has also been shown to allow for a more comprehensive proteomic sample profile than is possible with collision-induced dissociation alone, and it can be used to fragment and analyze large peptide fragments as well as intact proteins. For more on this, watch the webinar on ETD, accessible via https://advion.on.raindance.com/confmgr/view_stored_doc.jsp?docId=91034398541673712044526654961&docType=recording 

Spectroscopy has changed so much since I was in school. So has biotech.  HELP!

-AMS