News on trends and issues in the biopharm and pharmaceutical industry. Commentary on current events,clinical pipelines, facility expansions, competition, technology, legal and economic matters. M&A and licensing activity across the globe.
I am a Director of Research and Devopment for a leading supplier to biopharmaceutical producers. The views expressed are mine. I do not speak for any company or corporation.
I'd like to promote another blog by my colleague Mike Mitchell that discusses topics dealing with management of the supply chain among other things - and is geared toward the biotechnology industry. Enjoy.
I came across this cool site called CMO Locator by Kymanox. It allows you to find CMOs among its registrants who have the capabilities that you are looking for to execute your project. For example you might designate a need for a CMO that can meet following needs - mfg drug substance API, platform cell culture, scale 2000-5000 L, fed-batch process, phase I/II compliance, biosafety level 3.
The tool will spit out a list of CMOs matching those criteria.
Scientists in the SAFC Biosciences Cell Science and Development (CSD) department have pubished a new paper on a novel sialylation gene in CHO, called neu 3. The group confirmed neu 3 functionality by knocking it down with siRNA and shRNA to suppress gene function. They confirmed a model gamma interferon increased in its degree of sialylation under these conditions. This will come out in Biotechnology and Bioengineering. Lead authors for this study were Min Zhang and Scott Ross.
Since we are located very near Kansas City, and Stowers Institute is a neighbor, I felt compelled to pass this story along. Liheng Li's lab (say that fast 3x) reported (GEN) a novel theory for how stem cells are regulated in mammalian tissues.
I can't always write about science. Mostly, because my feeble mind can't create content fast enough to keep up with the rest of the world. So, I’ve decided to add a few fun things to the blog.
Once a month I will add a recipe.The only criteria will be that it is something that I actually like and have made myself - usually multiple times.Therefore in most cases, it will also be pretty easy to accomplish for most people. Enjoy!
Can I stop now? Can you figure out rest or do I need to provide operating instructions?
Melt butter in a thick-bottomed pot or Dutch oven, cook the sausage and ham until lightly browned, and stir in flour. Add the onions, scallions, green peppers, and garlic, and cook until vegetables are soft and transparent.Stir in the chopped tomatoes and their juice.Stir in the bay leaf, thyme, cumin, cloves, allspice, cayenne, and black pepper.Add the beef broth and mix well. Add the raw shrimp and the chicken. Stir in the raw rice. Season with salt, approximately a tablespoon to start. The liquid in the pot should just cover the contents.Add more broth if necessary (I’ve never had to add).Bring it to a boil, and then cut heat very low, cover the pot, and cook until rice is done. (The jambalaya should be moist when done but NOT soupy!).Adjust salt and serve at once.It will feed 8-10 hungry people – (or me and 5 people).
My favorite quote from the book, “Anybody who does not have a really good appetite should not be allowed to eat jambalaya”. I concur.
A good full-bodied red wine is recommended.I also like with beers that are fairly hoppy.And, I usually like to serve with fresh, hot corn bread.
I last made this for the New Orleans – Minnesota playoff game. So I can confirm that this recipe still works.Yum!
Pfizer updated analysts on its development pipeline - highlighting 16 vaccines and 27 biologics - a dramatic increase from its last update March 2009. Six "invest to win" areas were identified including: oncology, Alzheimer's, pain, inflammation and vaccines.
Fierce Biotech reported that Juvaris BioTherapeutics has attracted a new investor for its novel adjuvant technology and its lead candidate JVRS-100. This continues the interest shown in the adjuvant area with the resurgence of the vaccine market.
GEN recently noted this trend as well in its review of the vaccine market. Several newer adjuvants that are designed to produce greater immunogenicity than the more traditonal aluminum salts are making inroads. These include immunostimulators and microparticulate carriers, and may consist of more novel raw materials like cationionic lipids, squalene, and saponin as examples. Several new adjuvants are in clinical trials.
The MilliPROBE Detection System for Mycoplasma, the newest assay in Millipore’s MilliPROBE platform aimed at rapid microbial detection, cuts detection time from between 28 and 35 days (for traditional culture-based technology) to just four hours. Faster and more robust detection enables biopharmaceutical manufacturers to test more frequently and take corrective action earlier in the production process, reducing financial risks and optimizing product yields.
With a license to zinc finger nuclease (ZFN) technology, we now can create cell lines with enhanced properties rapidly and efficiently - markedly so as compared to homologous recombination techniques. Given the power, what genes would you knock out?
From a recombinant protein producers viewpoint, using CHO cells, we surmise genes like dhfr, GS, or fut8 and combinations thereof could expected to be popular choices. How about an endogenous host cell protein that co-purifies with your therapeutic? Or elimination of an endogenous viral sequence from your host cell?
Cutting Edge Information's Jason Richardson, CEO, predicts big challenges for pharma in next decade. Richardson says the blockbuster model is dead and mega-merger mania won't add value. He says the industry has not come to grips with fallacy of mega-merger business model - even though conventional analyst opinion holds that it is a waste of time and energy - and shareholder money.
A big challenge that we face in the Raw Material Characterization initiative is the development of good, sensitive bioassays.We not only want to show enhanced analytical profiles, we want to understand how, say impurities, affect biological performance or more subtly at what level does a particular impurity become a performance problem for the system.
So how are we going to do that?One idea is to identify multiple cell lines expressing model proteins that we can use in growth and productivity assays. We also will look at product quality. Likely, these will be CHO lines mimicking popular industry platforms but likely will not exclusively be CHO lines.Our goal is to then develop assays with sufficient throughput, sensitivity and reproducibility to be reliably used in screening and characterization of large numbers of raw materials. We’re testing our screening equipment with a scaled down model test system now.Our cell line selection is underway with a variety of parental CHO (DG 44, K1, etc) and non-CHO lines.
Medium selection is critical, as we don’t want it to mask component effects in our screening process. But the medium still needs to support cells over multiple passages and to support productivity.Screening our in-house medium library is a way to accelerate the process. In developing the assays, we need to determine suitable positive and negative controls.We can use a library of “bad” components to test the system.
To date, we have been able to qualify several cell lines that will work. We have several good positive and negative effectors. We have shown that known "bad" components can be detected in our assay system. We continue to extend and fine-tune the system. And, we're able to embark on biological characterization of our Top 100 raw materials.
Jim Miller predicts in his column in this month's Pharmaceutical Technology that big pharma will become an increasing competitor to CMO's in 2010 with at least one more big player, in addition to companies like Pfizer or Abbott, selling its excess commercial manufacturing capacity - including biologics manufacturing. See full article for other predictions.
GEN just published latest report from Rodman & Renshaw on status of Biotech financing in Qtr 4. Consolidation, secondary offerings and IPO activity all picked up. The prediction is that increased IPO activity and more successful secondary offerings will be seen in 2010.
As reported in PharmTech Talk's summary of new report from Biotechnology Information Institute, there were 16 new biopharmaceutical entities approved in 2009. This is up from 10 the prior year. Only 5 of these were from US based companies with the rest coming from Europe.
A recent JAMA article suggest this may be due to a decrease in R&D spending in US companies since 2003.
Bruce Carlson (Kalorama) writes that the world cell culture market reached $1.87 billion in sales in 2008 and is expected to grow to $3.4 billion by 2013, a CAGR of 12%. You can read more in the Jan 15th issue of GEN.
As an industry participant, I see Mr. Carlson's estimates as being a tad optimistic.
In creating our Raw Material Characterization initiative, one of the first steps was to identify and prioritize which materials to focus on.We used a risk factor weighting system to do this.Factors that we chose to consider in assessing our risk with each raw material were:
Frequency used in media formulations
Combined quantity and purchase costs percentile
Number of suppliers for that material
Raw material origin
Quality history with that component
Animal component containing status
Component complexity (simple or complex)
By making this assessment for each of the 400-500 raw materials that are used most commonly in the manufacture of our cell culture products, we derived a Top 100 list.Below, I’ve indicated the Top 20 items that fall on our list with our current criteria:
Folic acid USP
L-Tyrosine 2Na salt
L-Glutamic acid anhydrous
L-Cysteine free base
These raw materials will receive increased scrutiny in our new program as we endeavor to gain even tighter control using both analytical and biological assays - and subsequently driving findings back through our quality system and supply chain.
How does this compare to your situation?Who are your problem children?
Another scandal involving melamine adulteration of milk hit China this month as referenced by the Rx-360 website.
Because of similar incidents with other raw materials, this represents a not so subtle reminder as to why the FDA issued its guidance document for assessing melamine risk in pharmaceutical components, and further cited testing methods for that purpose.Methods for cleaning up complex samples to be tested have also been published.
I think all reputable suppliers applaud the FDA intent.Clearly, it is in everyone’s interest that the integrity of the supply chain be maintained.But, like many things, sometimes the devil is in the details.
The Coalition for the Monitoring of Melamine Adulteration (IPEC Americas, IPEC Europe, PhRMA, GPhA, CHPA, SOCMA) did issue a response citing some concerns and recommendations that should be considered prior to implementation (Download IonConsolidatedCommentsonMelamineGuidance9-9-2009(Final))IPEC further provides suggested templates to request information from suppliers in an attempt to standardize both the requests and responses with the intent of minimizing non-value added work.
Given the new situation, it is not surprising that suppliers and customers alike are feeling their way forward as to how to best address the FDA’s guidance.We’ve surveyed the scene and have the perhaps unique perspective of being both a supplier and a customer for a wide variety of raw materials used in a host of industries – not just the pharmaceutical industry.Certainly, the responses we’ve seen are mixed too.
Accordingly, we’ve tried to take a risk-based approach that helps us to concentrate our testing efforts on those materials that would have the biggest risk of melamine contamination and that would otherwise go undetected, and those materials that would have the biggest potential impact on product safety.
Our Risk Assessment concept follows.I would like to receive feedback on this from our customers, suppliers and the market generally.
I’d like to describe major elements in the Raw Material Characterization program as it is currently conceptualized.I do expect it to evolve and be modified as we learn more during development and implementation.Right now we have seven projects identified that form our backbone.
Project 1:Development of a Searchable Database
Create a common database with the ability to search for correlations between characteristics of raw materials and biological or physical effects.Create additional capability to determine similarity of formulations and developing “media family trees”.
Search capabilities to link assay data with formulations or components
Ultimately develop a customer web accessible database with links to raw materials used in media
Project 2:Developing a Prioritized List of Raw Materials
Develop criteria to create prioritized list of raw
Rank raw materials and develop a “Top 100” list for initial characterization work
Project 3:Development and Verification of Analytical Assays
Develop sensitive analytical assays to characterize raw materials, contaminants and changes in recombinant protein product quality
Detect chemical differences in raw materials that may affect performance
Project 4:Development and Verification of Biological Assays
Develop sensitive and reproducible biological assays to detect changes in cell culture growth, productivity and product quality
Detect biological differences in cell culture growth, productivity and product quality
Correlate observed differences with biological performance
Project 5:Drive Specifications
Reduce variability in media performance by controlling specifications.
Recommend new specifications to minimize risk of contaminants identified via analytical and biological testing
Project 6:Physical Effects of Raw Materials in Complex Media
Create database predicting chemical reactions and solubility limits for mixtures of raw materials
Use information to improve stability of formulations
With improved predictability, reduce cycle times for concentrate feasibility assessment
Project 7:Biological Effects of Raw Materials in Complex Media
Improve methods for media development by better understanding the biological effects of raw materials in complex media
Create database predicting the effects of raw material changes on media performance and metabolic pathways
Provide an enhanced understanding of risk associated with medium formulations
Our goal is to be more empirically driven.We want to thoroughly understand our products and processes.We’d plan to use that information to create more robust products, increase the speed of our product development, and to provide greater product related support to our customers.Ultimately, we will increase our ability to manage product (raw material) related risk and provide greater transparency to our customers.
My next post will address aspects of biological testing.
As mentioned in the previous post, the Raw Material Characterization initiative came out of our customer interview process. But we were bolstered in our resolve to institute this program based on several other factors that have occurred in past couple years.
The regulatory agencies have put a much higher premium on characterization and traceability of raw materials used in the manufacture of pharmaceuticals and biopharmaceuticals. The issues with China sourcing for example are well described. Clearly more responsibility for making this assessment has been placed on the drug manufacturer and all other members of the supply chain. I see it as our responsibility as a critical raw material supplier to marketed drugs to actively improve our capabilities in this process. Institution of the Raw Material program is one of several means we are employing to do this.
Additionally, we have seen first hand several examples of raw material problems that resulted in performance issues for our customers in their production systems. Examples include:
1. Carryover of a cleaning agent in a soy hydrolysate from one of the major manufacturers. Interestingly, the change was considered to be non-critical by the hydrolysate manufacturer and no change notification was issued. This particular incident was insidious in nature, as the detergent’s effect on cell culture seemed to be cell line, clone and protein specific. Customers observed a spectrum of effects from nothing to overt toxicity. We instituted a new analytical screening assay for incoming lots of this raw material and put corrective action plan in with vendor.
2. Solubility issues with certain amino acids like cysteine and tyrosine. We have proven to ourselves that not all amino acids are equal. A recent study of tyrosine examining multiple lots from multiple (>5) vendors showed that material from one vendor exhibited significant solubility/toxicity problems. We disqualified this vendor as a provider of this material. Conversely, we’ve also identified alternative forms of both amino acids that have greatly increased solubility properties and are very useful in feeds or concentrates.
3. PVA filterability issues in medium. Again, we’ve observed significant lot specific variance with PVA. This is both vendor to vendor variation as well as lot variation within a single source. We’ve instituted an extensive characterization program to look at physical and chemical properties (e.g. mean particle size, crystalline structure, viscosity of 4% solution, % hydrolysis, MW) of PVA to correlate with filterability characteristics. We’re also examining the use of other grades of PVA as a possible solution.
4. Trace contaminants in hydrolysates, amino acids, etc. Often these can be tied back to the presence of things like trace elements. If these products are being added to cell culture media, this level of variability can result in marked performance issues – growth, productivity, and protein quality.
5. Presence of a manufacturing bioproduct in the biological buffer BisTris. We were able to identify this through analytical testing and to eliminate the problem with a process modification. This was possible for us as we are a primary manufacturer of BisTris even though were not the original manufacturer of the problem material. The assay could then be used to confirm the problem was alleviated.
Other examples could be cited as well but this gives you a flavor.
Our Raw Materials Characterization Program is designed to thoroughly characterize our raw materials, identify risks that could affect performance of our media products and develop strategies to minimize those risks.
The goal/deliverable of the Raw Materials Characterization Program is to develop a best-in-class knowledge base of the raw materials used in our formulations and their impact on performance of our products.
This program will consist of three phases with multiple projects envisioned during each phase. The first phase will develop the support structure needed to successfully perform the studies in the next two phases. The second phase will focus on characterization of individual raw materials while the third phase will evaluate raw material effects in complex media.
Phase I: Initial Support Projects · Development of a searchable database · Prioritized list of raw materials · Development and validation of analytical assays · Development and validation of biological assays
Phase II: Characterization of Raw Materials · Characterization of contaminants in raw materials · Characterization of complex components · Characterization of simple components
Phase III: Characterization of Raw Materials Effects in Complex Media · Physical effects · Biological effects
Next post will discuss projects within the program in more detail.
We (myself & 5 team mates from marketing & our R&D group) recently interviewed 30+ customers in leading biotechnology & biopharmaceutical manufacturers. All of these individuals came from companies that have active development pipelines with new bio-molecules and also have existing biopharm products approved and on the market.
I was interested in determining what products/services these customers were interested in from a bio-developer/manufacturers point of view. And more specifically, from a Company like us that provides services like these to biopharm companies utilizing cell culture as their production platform. Further, we were interested in what we could do from a technical perspective to enhance their experience with us as a vendor or partner (the latter being our preferred relationship).
The number one item selected by these customers – whether they were in the process development, manufacturing, or quality function – was that they wanted better characterization of raw materials in the products that we sold them. Usually customers were talking about cell culture media & feeds in this context but in other cases may have been considering other parts of the process downstream from the bioreactors.
What did better characterization actually mean?
Like most things in this industry that varied by customer. However, certain themes did emerge.
1.Know how the raw material/component performs in your product & how changes in that raw materials might effect that product’s performance
2.Know how changes in a raw material might effect performance of your (my) product with my [customer’s] production system & ultimately their end product
3.Understand key performance criteria of each raw material
4.Understand critical specifications for that raw material as relevant to end user applications not necessarily only to a pharmacopoeia standard for example
5.Provide both analytical testing results and biological performance & correlate the two in a meaningful fashion related intended application
6.Understand issues around chemical forms (e.g. free base or salt) and physical forms of the material (powder, liquid, concentrate)
7.Provide information around manufacturability (e.g. how solubility characteristics might effect this)
8.Provide information around compounding (i.e. ability to include component in a formulation and how to do that so that is stable and effective)
Raw material characterization was cited as an opportunity that every supplier in the industry could improve upon. Every customer I spoke to indicated they would like to see more work done in this area and more transparency around the resulting data/knowledge base. Clearly, customers would also like to see this concept integrated with the whole supply chain management around raw materials.
Based on this feedback, we have embarked on a “Raw material characterization” initiative. I would like to spend the next several posts describing some of our approaches and early observations.