Social media has changed the way people and organizations communicate. Platforms like Twitter and Facebook have demonstrated that they can be effective tools for widespread communication of emergency instructions during natural disasters and in organizing political change in countries with censored media. Social media outlets, however, have limitations when asked to deliver complex, technical information. In addition, the open platform nature of the Internet presents challenges for companies trying to maintain correct information about their products online.

FDA in June proposed two draft guidances that share the agency’s current thinking about how drug and medical device manufacturers can accurately communicate about their products online.

Guidance for Industry, Internet/Social Media Platforms with Character Space Limitations--Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices (1) provides recommendations for conveying information about a drug on social media platforms such as Twitter or paid search results links. While the 140-character limit of Twitter may be enough for the latest life updates from figures in popular culture, it will be difficult for drug companies to use the platform under FDA’s proposed guidelines. 

In the guidance, FDA notes: “… regardless of the platform, truthful, accurate, non-misleading, and balanced product promotion best serves the public health. For some products, particularly those with complex indications or extensive serious risks, character space limitations imposed by platform providers may not enable meaningful presentations of both benefit and risk … If an accurate and balanced presentation of both risks and benefits of a specific product is not possible within the constraints of the platform, then the firm should reconsider using that platform for the intended promotional message.”

In the draft guidance, FDA indicates that a drug’s risk information must be presented with benefit information in the same limited-character message, such as a tweet. The risk information should include the most serious risk associated with the drug. In addition, a mechanism, such as a hyperlink, must direct people to more information about risks. That is a lot of information to get into 140 characters.

In Guidance for Industry, Internet/Social Media Platforms: Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices (2), FDA explains that drug companies generally are not responsible for comments from third parties who are independent of the drug company that are posted on the company’s website forum, an independent website, or in social media. If a firm voluntarily and truthfully undertakes the correction of misinformation that is within the scope of the guidance, “FDA does not intend to object if these voluntary corrections do not satisfy otherwise applicable regulatory requirements, if any,” the draft guidance reads. 

FDA cites the growing the role of social media and notes that the guidance was developed with the best interests of the patient in mind. However, the task of maintaining proper information about regulated products in an unregulated environment may be too great a challenge for FDA or drug companies to manage. 


  1.	FDA, Guidance for Industry, Internet/Social Media Platforms with Character Space Limitations--Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices, Draft Guidance (Rockville, MD, June 2014).
  2.	FDA, Guidance for Industry, Internet/Social Media Platforms: Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices, Draft Guidance (Rockville, MD, June 2014).


Rita Peters is the editorial director of 

Articles

From the Editor

FDA draft guidances seek to maintain accurate drug information in new media.

Benefits and Risks of Drug Information on Social Media

The value of the customer relationship to a CMO is a function of two variables: unit volume and price per unit.  Both variables are contentious issues: bio/pharmaceutical companies are putting enormous pressure on their CMOs for lower prices, while their inability to deliver forecasted volumes often means lost revenues for CMOs as reserved capacity goes unutilized. The resulting low margins depress CMO profitability and threaten their ability to raise capital and invest in replacement equipment and new facilities.

While low prices and missed forecasts often undermine the CMO-customer relationship, they reflect real challenges in the macro bio/pharma environment. Governments and private payers in North America and Europe are increasingly unwilling or unable to afford escalating expenditures on drugs. In Europe, governments have either pledged to reduce drug expenditures by national health plans or limit the growth of those expenditures to less than 5% annually. To ensure that budget targets are met, drug companies are forced to rebate some of the revenue realized from sales to national health programs when those purchases exceed targeted levels. 

In the US, there has been much press attention to the rapid rise in list prices for drugs, but the reality is that those list prices do not reflect what drug companies actually receive from their sales. A recent analysis by investment firm Credit Suisse found that major bio/pharma companies must give back 25-50% of the drug price in the form of discounts or rebates (1). Health insurance companies are getting tougher when negotiating pricing and are pushing more of the costs onto patients in the form of higher co-pays. 

A growing risk for bio/pharma companies is that a drug won’t get covered at all. Payers are increasingly asking whether the incremental benefit of a new treatment is worth the high prices that bio/pharma companies are asking for new medications, especially cancer treatments. This development directly threatens the revenues and profits that bio/pharma companies expect their new product pipelines to be generating in the future.
  Europe, especially the UK and Germany, is leading the way in restricting formulary access for new drugs. The leader in this process has been the UK’s National Institute for Clinical Excellence (NICE). NICE evaluates drugs for inclusion on the approved formulary of the UK’s National Health Service based on an analysis of clinical benefit relative to cost.

A recent PharmSource Trend Report found that NICE rejected 50% of the new oncology drugs it reviewed in the 2009-2013 period. Another third of oncology drugs were granted “Conditional Recommendation,” meaning they would be reimbursed only for limited indications and/or with substantial discounts. Only 17% of oncology drugs reviewed during the 2009-2013 period were granted a full recommendation. Among non-oncology drugs, one-third received an outright recommendation for coverage but over half received a conditional recommendation (2).

While NICE does not set actual prices in the UK, its counterpart in Germany, the Institute for Quality and Efficiency in Health Care (IQWIG), does. Drugs that are deemed not to deliver additional clinical benefit are priced at the level of the comparator drugs already on the market, which are often generics. Bio/pharma companies have withdrawn some innovator drugs from the German market after receiving an evaluation of no additional benefit because they were unwilling to accept payment at generic-drug price levels

Evaluations of new drugs by IQWIG have been similar to those by NICE. During the period 2011-2014 (first three months), IQWIG determined that 50% of the new drugs presented to it offered no additional benefit relative to drugs already on the market. A third were deemed to offer minor or non-quantifiable benefits, and only 10% were found to offer considerable benefit (2).  


Decisions limiting or rejecting coverage for new drugs have hit CMOs hard. PharmSource analysis found that the nearly 60% of the rejected or limited drugs use a CMO for drug manufacture, and a similar percentage use a CMO for API manufacture. PharmSource estimates the lost CMO revenues amount to at least $250 million per year, and probably more: NICE and IQWIG evaluations are referenced by most other European countries, and even by Japan.

Drug companies and CMOs will take an even bigger hit as the US catches up with Europe in the evaluation of comparative effectiveness. The furor over the cost of Gilead’s Hepatitis C treatment Sovaldi (contract manufactured by Patheon) has focused heightened attention on the cost/benefit trade-off. In recent months, the American Society of Clinical Oncology has begun its own initiative to evaluate the cost effectiveness of alternative cancer therapies as guidance for oncologists.

In the face of this increasingly difficult macro environment, how should CMOs respond? Their first response should be defensive by doing rigorous due diligence when determining pricing and contract terms for new drugs, especially new molecular entities. They need to understand whether the sponsor’s expectations regarding price and volume are realistic given the high performance benchmarks erected by payers. They should be familiar with the coverage decisions that have been made regarding similar drugs, and they need to satisfy themselves that sponsors have reflected pharmaco-economic factors in clinical trial design and marketing plans. 

Where coverage risks are high, CMOs may want to insist on take-or-pay or volume-based tiered pricing schemes to assure themselves a level of protection against adverse coverage decisions. They must also be relentless in their efforts to drive down their operating costs to protect their margins.

Price pressures and coverage limitations are immutable elements of the bio/pharma industry’s macro environment. CMOs need to reflect those realities in their processes and operations if they are to succeed.


  1.	S. King, “FirstWordLists: Which companies pay the highest US rebates and which companies are most dependent on US drug price increases?” www.firstwordpharma.com, May 11, 2014. 
2.	PharmSource, “Not So NICE: How Market Access Schemes in Europe are Impacting the CMO sector,” (May 2014). 


Jim Miller is president of Pharmsource Information Services, Inc., and publisher of 

, tel. 703.383.4903, info@pharmsource.com. 

Perspectives on Outsourcing

As payers refuse to cover new drugs, CMOs take a hit.

Health Systems Raise the Bar on Reimbursing New Drugs

Applikon Biotechnology’s micro-Matrix technology platform for the handling and growth of large numbers of microbial strains, clone libraries, mutant banks, and cells is easy-to-use and cost-effective. The system offers 24 independent bioreactors in a microtiter plate footprint. pH and dissolved oxygen can be controlled in each individual bioreactor via gas and liquid addition. Temperature is controlled individually in each bioreactor by the integrated cooling and heating system. The micro-Matrix offers a scale down of small-scale bioreactors. The bioreactor’s square well cassette design is based upon SBS-format microtiter plates, which integrate into lab automation robots. According to the company, the PC-based interface offers an intuitive interaction for advanced process control in each of the 24 bioreactors. 



Products

Microbioreactors Increase Productivity

ATCC has expanded its solutions for mycoplasma quality control to include quantitative mycoplasma genomic DNA prepared as Certified Reference Materials. These preparations support its range of quality control products, which include the Universal Mycoplasma Detection Kit and a collection of 10 titered mycoplasma reference strains. ATCC Certified Reference Materials are calibrated to one or more specified properties, making them useful in challenge assays, verifying or comparing test methods, and benchmarking assay performance during assay validation or implementation. Quantitative mycoplasma DNA Certified Reference Materials were isolated from strains most frequently associated with cell culture contamination, and were quantified for genome copy number using digital PCR-based technology.

Quantitative Mycoplasma DNA Offers Quality Control

The promise of precision medicine is beginning to bear fruit as deadly diseases are made treatable, doctors use genetic information to guide treatment decisions, and the convergence of information, communications, and biological technology reinvents the practice of medicine. The arrival of this new age of medicine has captured the imagination of investors, who are pouring record investments into these emerging areas. Privately held life-sciences companies have raised $7 billion through the first five months of 2014, representing a 36.2% increase compared to the same period last year. Investment in early-stage companies drove the increase as seed, series A and series B investment jumped 182% during the period to $2.9 billion. The surge in funding is going into innovative areas such as gene therapy, immune-oncology, and digital healthcare technologies that promise to move the needle on the delivery of care and improve outcomes for patients with once-intractable diseases.

As Big Pharma shifts its resources away from internal R&D to externalizing innovation, investors see opportunities in backing companies with cutting-edge technologies. And venture investors, boosted by liquidity from the robust capital markets, are backing startups up with adequate funding to allow them to validate their technologies rather than needing to constantly seek new capital. 

Over the past year, investors have pumped more than $2 billion into gene therapy, immunotherapies, and digital-health companies, including more than $1.3 billion invested in startups and $819 million raised by nine companies through initial public offerings (see 

). Almost every big pharmaceutical company with an oncology program is developing cancer immunotherapies, while companies focused on genetically inherited diseases are exploring gene-therapy solutions.


  Venture investors and Big Pharma took notice of the potential of gene therapy after a team of researchers at the University of Pennsylvania, led by Carl June, published results of a small trial of their chimeric antigen receptor T-cell (CART) cancer-killing cell therapy in August 2011 that showed complete remission from chronic lymphocytic leukemia in three patients who no longer responded to chemotherapy. 

That led to a historic partnership between Novartis and the University of Pennsylvania aimed at bringing the new personalized immunotherapy approach to patients with various forms of cancer. Novartis invested $20 million for the construction of a new research center in Philadelphia as part of the pact, and gained an exclusive worldwide license to the technology developed at Penn that uses manipulated immune-system cells to kill cancer cells. Using genetic engineering, June’s team manipulated T cells extracted from leukemia patients into recognizing and attacking leukemia cells. These altered T cells were re-injected, using a deactivated HIV-1 virus, into the patients where they proliferated until they destroyed the cancer cells. 

At the time, June told reporters that multiple drug makers and many venture investors were interested in the “ultra-personalized” therapy. He chose to work with Novartis because he felt the therapy was likely to reach patients faster with an already existing company. 

June isn’t the only scientist experimenting with CART therapy to attack cancer. In early December 2013, three leading cancer centers--The Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center, and Seattle Children’s Research Institute--joined forces to launch Juno Therapeutics in Seattle. Arch Venture Partners and Alaska Permanent Fund pledged an initial investment of $120 million, with Amazon’s Jeff Bezos and others adding another $56 million in 2014, making it perhaps the largest series A funding of a life-sciences company to date. 

Juno’s cofounders include Richard Klausner, a former director of the National Cancer Institute, and Juno CEO Hans Bishop, who helped build Dendreon’s process of using a patient’s own T cells to induce an immune response in cancer. Other companies in the space include Bluebird Bio and Kite Pharma. 

Investors are also launching companies developing gene therapies using adeno-associated vectors to modify genetic defects to treat otherwise irreversible conditions. In October 2013, the Children’s Hospital of Philadelphia (CHOP) committed $50 million in seed funding to launch Spark Therapeutics to advance its gene therapy clinical trials and commercialize its technology. The financing came after more than a decade of work at CHOP perfecting the necessary tools to allow routine translation of gene therapy from bench to clinic: the gene delivery vector itself, and the manufacturing of clinical-grade vector using good manufacturing practices. 

Besides its agreement with CHOP, Spark is working with other academic institutions to assemble the technology, programs, and capabilities needed to deliver its first gene therapy products.  These include gene therapy to correct the gene for clotting factor IX, defective in patients with hemophilia B, for use in an early-stage clinical trial. They are also pursuing a gene therapy to correct a gene defective in one form of inherited retinal degeneration that ultimately causes irreversible blindness, for use in a late-stage trial. In late May, Spark raised another $72.8 million in a series B round from venture investors and several healthcare funds.

Researchers are also working with bacterial proteins that allow them to cut DNA in specific places to edit disease-causing genes. Cambridge, Massachusetts-based Editas Medicine launched in November with $43 million in a series A financing to translate its genome editing technology into therapeutics. Genome editing technology has come a long way, making it now possible to precisely modify almost any gene in the human body with the ability to directly turn on, turn off, or edit disease-causing genes, says the company, whose five co-founders include Harvard’s George Church, MIT’s Feng Zhang, Harvard University’s David Liu, Harvard Medical School’s Keith Joung, and the University of California, Berkeley’s Jennifer Doudna.


  Investment is also ramping up in innovative digital technologies that aim to transform the delivery of healthcare. Three recent financings attest to what investors see as the power of technology to modify health. 

Flatiron Health, a company developing an oncology platform to improve cancer care, raised $130 million in a series B financing round led by Google Ventures. Its cloud-based platform aggregates and transforms clinical and financial data from electronic medical records and billing systems in real-time, allowing the industry to have a comprehensive view of a patient’s experience in the oncology office as it happens. 

NantHealth, launched by billionaire Patrick Soon-Shiong, raised $135 million from an undisclosed sovereign wealth fund in a series B financing round. NantHealth says it is in the intersection of innovation and connectivity, building a platform that will integrate data streams to allow for better healthcare delivery and outcomes. 

And Proteus Digital Health, a maker of digital pills—miniature ingestible sensors that track vital signs, raised $120 million from undisclosed global institutional investors. These digital medicines integrate drugs with ingestible, wearable, mobile devices, and cloud computing in order to deliver solutions that enable patients, their families, and their doctors to make better decisions about their health. 

These are a number of the innovative, precision technologies that likely will be coming onto the market over the next few years that have the capability of improving how health decisions are made, how care is delivered, and how patients are medicated, all with the potential of transforming healthcare. 

G. Steven Burrill is chief executive officer at Burrill Equities, San Francisco, CA, 415.341.3870, steve@burrillequities.com. 

Burrill on Biotech

Gene therapy, immune-oncology, and digital healthcare technologies offer investors promise for innovation investments.

Moving the Needle on Healthcare

A critical quality attribute (CQA) has been defined as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality” (1). Biotech therapeutics, particularly complex products such as monoclonal antibodies (mAbs), can have numerous quality attributes that can potentially impact safety and/or efficacy of the product (2). Identifying CQAs for a biotech therapeutic is the first and arguably the most difficult step in implementation of quality by design (QbD) for development and production of biopharmaceuticals (3, 4). 

Even if a firm chooses not to pursue intensive studies to map out complete design spaces for their manufacturing process, and instead opts for what the International Conference on Harmonization (ICH) Guideline Q11 refers to as a “traditional approach,” the ability to differentiate between what is and is not important for a molecule can drive sound decision-making in process development, which can lead to improved efficiency, cost savings, and more consistent product quality (5). And for those sponsors who do embrace a more comprehensive, “enhanced approach” to development, a solid understanding of product quality attributes serves as the touchstone upon which process design and integrated control strategies are built.

Structural characterization is used to assess the CQAs of biopharmaceutical products. The structural data must be supported by functional data to establish a structure-function relationship. In turn, these data can then be used to define the structural components’ impact on the activity of the product. Furthermore, the characterization data obtained are essential for product development and regulatory acceptance. Characterization of multiple product batches is essential to demonstrate to the regulatory body that the manufacturer has control of the manufacturing process. This is achieved by analyzing a number of batches of product and comparing the data. Significant differences between batches need to be investigated and their impact on the function of the product assessed. This comparison in the QbD paradigm also centers around the CQAs. 

The European Medicines Agency’s guideline covering “Production and Quality Control of Monoclonal Antibodies” requests that “the mAb should be characterized thoroughly” (6). “This characterization should include the determination of physicochemical and immunochemical properties, biological activity, purity, impurities, and quantity of the mAb, in line with ICH Q6B guideline” (7). The EMA mAb guideline also draws attention to a number of structural features including N- and C-termini (in particular pyroglutamic acid at the N-terminus and lysine at the C-terminus of the heavy chain), free sulfhydryl and disulphide bridge structure, glycosylation (in particular the degree of mannosylation, galactosylation, fucosylation, and sialylation), and other post-translational modifications (e.g., deamidation, oxidation, isomerisation, fragmentation, and glycation).

In this 30th article of the “Elements of Biopharmaceutical Production” series, the authors focus on proposing an approach towards establishing CQAs for a mAb therapeutic product. 


  Identification of CQAs is often performed through a series of product risk assessments conducted over the program lifecycle, the first of which should be performed early in development to bring clarity to the goals of the Phase I process (4). Although the criticality of some attributes at this stage may still be somewhat based on speculation, these “potential CQAs” (pCQAs) serve as both a baseline for development to proceed and a gap analysis to identify which attributes would benefit from further 

 studies to ascertain their true impact on efficacy and safety. As the molecule progresses through development and more is learned about the relationship between product attributes and their impact (or non-impact) on potency, pharmacokinetics (PK), or safety, these pCQAs can be further refined and accordingly designated as CQAs as the product approaches the licensure application.

Because assigning criticality to an attribute hinges upon the question of risk posed to product safety and efficacy, a well-rounded product risk-assessment team should include representatives with expertise in PK, toxicology, 

 biology, and clinical management. A risk-ranking and filtering approach developed on the firm’s experiences and regulatory feedback may be used. Many such tools have been presented in the literature, and a firm can pick a tool of their choice as long as the basis is rational and it has been justified that the tools are used consistently (8, 9). The risk-assessment team first compiles a list of all the quality attributes of the product and systematically evaluates each attribute with regards to two factors: impact and uncertainty. 

For impact, the team determines the severity of the consequences that would be associated with failure to control the attribute. The team considers the effects of the attribute not only on potency with respect to the intended mechanism of action, but also PK, pharmacodynamics (PD), immunogenicity, off-target effects, and direct impact to safety. The data used in the impact assessment may come from structure-activity relationship (SAR) studies, nonclinical studies, clinical exposure history, and toxicology reports (4). For platform molecules, or new products with structural homology to established classes (e.g., Fc fusion proteins, pegylated proteins), the team can leverage information from related proteins. Conversely, the more novel the protein is, the less opportunity there may be to apply knowledge across products.

After assigning an impact score, the team then evaluates the quantity and relevance of the body of data used in its assessment and assigns an uncertainty score to the attribute. The team considers its degree of reliance on 

 data, the availability of molecule-specific data pertaining to potency and PK, the relevance of data leveraged from related molecules, and the range of clinical exposure. Process additives undergo a similar assessment, which focuses on the sufficiency of toxicology data and the additives’ history of use. In general, the assessment of product quality attributes for novel proteins will have a higher degree of uncertainty than platform molecules in early development. For these products, one should strongly consider conducting the initial product risk-assessment exercise early in the development cycle to align the organization on a commonly-recognized target product profile. Otherwise, cell culture, purification, and drug product development may put undue importance on meeting certain criteria that are ultimately not critical, resulting in suboptimal processes that make unnecessary trade-offs between attributes.

Once the impact and uncertainty scores have been assigned, the product of these two values constitutes the risk priority number (RPN) for the attribute (9). Although the scoring system may define a numerical threshold for which attributes would receive a CQA or pCQA designation, the degree of confidence in assigning the impact and uncertainty scores must be kept in mind to avoid over-interpretation of the analysis. Instead, the authors have found that viewing a product’s quality attributes from a more holistic view, using the scores to generally characterize their degree of criticality with labels such as “high,” or “moderate-to-low,” is preferable (4). This is also consistent with guidance from regulators, who encourage firms to view attributes as lying along a “continuum of criticality,” in which attributes warrant different degrees of control depending on how critical they are and how readily they can be controlled through the process. It should be highlighted that while an attribute can be “less critical”, it does not mean that a control strategy is silent with regards to its control; every attribute requires a control strategy commensurate with its degree of risk.

It is also important to note that within the context of a product risk assessment, it is generally a good practice to exclude process capability considerations and the extent to which they can mitigate the risk. The fact that a highly critical attribute is easily controlled through the process, even to the point of not requiring routine testing, should be captured separately in process risk assessments and in the overall control strategy design and justifications. By evaluating attribute criticality solely on the basis of impact and uncertainty, the product risk assessment only needs to be revised when new information is discovered regarding the biology or toxicity of the attributes themselves, and not every time a process change is made (8).

In general, the pCQAs identified in the initial product risk assessment fall into two categories: 

pCQAs that are known or are highly likely to directly impact safety or efficacy will ultimately become CQAs. Attributes such as residual host-cell proteins, endotoxin, protein aggregates, and biological potency, which may initially be assigned as pCQAs during Phase I development, are highly critical in such a fundamental way that no amount of additional experimental study will alter their assignment as CQAs later in development. 

pCQAs whose impact on efficacy is unknown or uncertain will likely be the main focus of CQA determination studies. These are attributes whose criticality can vary on a molecule-by-molecule or class-by-class basis, and therefore, can benefit most from further experimental studies to accurately define their impact to product performance. These attributes typically include post-translational modifications and stability-indicating chemical changes to the molecule, such as glycosylation, charge isoforms, phosphorylation, oxidation, and deamidation.

Mass Spectrometry for Molecular Weight Measurement and Peptide Mapping


  Intact molecular weight measurement and peptide mapping are routinely used to assess and compare the protein backbone of the light and heavy chains of mAbs (10, 11) and can be valuable tools in determining product CQAs. Intact molecular weight analysis using high end quadrupole-time-of-flight (Q-TOF) mass spectrometers is able to produce mass accuracy within a few Daltons for intact mAbs. This information, coupled with analyses following reduction and de-N-glycosylation, allows an initial assessment of the intactness of the product and a number of the post translational modifications present on the molecule. 

 shows the total ion current (TIC) chromatogram obtained from on-line reverse-phase, high-performance liquid chromatrography with electrospray mass spectrometry (RP-HPLC/ES-MS) analysis of a mAb.

A transformed electrospray mass spectrum created from m/z data acquired during elution of the peak observed at 24.85 minutes is shown in 

. These data combined with the data obtained from analysis of the mAb following reduction, and the heavy chain component following de-N-glycosylation (transformed mass spectra shown in 

), allow the intactness of the mAb to be assessed. The data also provide an overview of the N-linked glycosylation, allow an assessment of the level of C-terminal Lysine (at the C-terminus of the heavy chain) and also suggest, for this particular product, that a portion of the heavy chain exists in glycated form. These analyses provide a significant amount of information from rapid and relatively straightforward experiments. The data obtained from analysis of the CQAs of further batches or reference materials in parallel can be used to provide an assessment of comparability in terms of batch to batch or indeed biosimilar to reference medicinal product.

Peptide mapping is normally used to confirm these assignments and also allow further assessment of the protein backbone, particularly for post translational modifications. 

 shows the basic process comprising reduction/alkylation, digestion, and enzymatic release of peptides (and glycopeptide) from a mAb for analysis.

The products of digestion are usually analysed by on-line LC-MS. The TIC data obtained from peptide mapping of two batches of mAb are shown in 

 and allow a visual comparability assessment to be made.

Low energy (for peptide molecular weight) and high energy (for sequence assessment) mass spectrometric detection of the peptides during elution allow a further two dimensions of analysis. The data produced also allow a comparability assessment of the N- and C-termini of each chain (in particular presence and relative levels of pyroglutamic acid at the N-terminus and lysine at the C-terminus of the heavy chain), free sulfhydryl and disulphide bridge structure (from a comparison of reduced and non-reduced digests), glycosylation (in particular the degree of mannosylation, galactosylation, fucosylation, and sialylation), and other post-translational modifications (e.g., deamidation, oxidation, isomerization, fragmentation, and glycation).

Gaining Product Knowledge Through SAR and Pk Studies


  For platform-driven molecules, such as mAbs, a pre-established set of pCQAs can often be applied across programs, but care must be taken to ensure that they are relevant to each new molecule under development. For example, as part of early-stage product characterization, a new mAb was tested to determine whether its susceptibility to methionine oxidation was typical to that of other platform mAbs. 

 illustrates the levels of site-specific methionine oxidation measured by LC-MS peptide map in the presence of increasing concentrations of an oxidizing agent. This study found that although the two conserved methionine residues in the Fc domain were prone to oxidation, the most susceptible methionine residue was located within the complementarity determining region (CDR). This finding prompted additional follow-up to determine the criticality of oxidation at the CDR site. Oxidized preparations of the mAb were prepared, characterized to ensure suitability of use (i.e., lack of extensive aggregation or fragmentation), and were then submitted for potency testing by binding assay. As shown in 

, preparations of the mAb containing up to 78% oxidized methionine at the CDR site were found to be equipotent to unstressed control material, providing assurance that this product quality attribute was not a critical determinant of product activity.

When SAR studies are conducted with legacy programs, the longer history of product development can be turned to one’s advantage, especially if multiple cycles of process development can provide a valuable source of materials for study. For example, terminal galactosylation was identified as a pCQA for a mAb, largely due to a high degree of uncertainty regarding its impact on efficacy. Because the levels of biantennary had changed over the course of development, archived materials could be incorporated into SAR studies to investigate CDR binding and FcγRIIIa binding activities with the drug substance lots actually used in Phase 1 studies. With agalactosyl (G0F) glycan levels from 36-75% adequately covered by clinical materials, only a hypogalactosylated preparation of the mAb (via galactosidase digestion) was needed to help supplement the study. 

summarize the results of these studies. It was found that CDR binding activity was unaffected by galactosylation of the Fc glycan, while FcγRIIIa binding activity decreased modestly with increased G0F content, consistent with literature reports. On the basis of these data, as well as the extensive clinical history that was established and the wealth of relevant literature, Fc glycan galactosylation was deemed to be a moderately critical quality attribute for this molecule.

Assessing the impact of an attribute on PK can be challenging if the attribute of interest is inherently microheterogeneous, such as glycosylation. But in some cases, powerful analytical tools such as mass spectrometry, can be employed to deconvolute the results of PK studies conducted with heterogeneous source materials. To study the effects of glycan structure on the clearance of an Fc receptor fusion protein, an affinity extraction method was developed that could specifically recover the drug from cynomolgus monkey serum samples collected at various timepoints. Quantitative mass spectrometry was then used to determine whether site-specific glycan profiles changed between timepoints, which would suggest preferential clearance of certain glycoforms. 

 illustrate the results from this study, which found that the criticality of glycan structure was highly site-dependent. The composition of glycans at the Fc site (see 

) was essentially unchanged over 22 days, with percentages of G0F, G1F, and G2F (biantennary glycans with 0, 1, or 2 galactoses) holding steady for the duration of the study. By contrast, 

 shows that the relative population of sialylated biantennary glycans on the receptor domain, such as A2G2F, increased slightly at the expense of the asialylated glycan G2F over time. This example underscores the importance of considering criticality for some attributes on a site-by-site basis; a given glycan (G2F) can be non-critical at the Fc, but moderately critical on the receptor.


  Product risk assessment can be a valuable tool to not only help direct the course of process development and control strategy design, but also to identify opportunities to gain better understanding of what is truly important about the molecule itself. Designed experiments, using well-characterized test articles and advanced analytical methods, can help resolve uncertainties surrounding attribute criticality. Ultimately, a clear picture of attribute criticality, followed by mapping of their linkages to process parameters, can enable well-justified, science-based control strategies that put the right controls at the points where they can be most effective in ensuring product efficacy and patient safety.


  The authors would like to thank Li Zang, Richard Strong, and Xiaoping Hronowski for their contributions to the SAR and PK studies cited in this publication.

ICH Harmonized Tripartite Guideline Q8: Pharmaceutical Development

, Step 4 version (August 2009).
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ICH Harmonized Tripartite Guideline Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

, Step 3 version (September 2011).
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Guideline on Development, Production, Characterization and Specifications for Monoclonal Antibodies and Related Products

, EMEA/CHMP/BWP/157653/2007 (December 2008).
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ICH Topic Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products

, Step 5 version (September 1999).
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Process Validation in Manufacturing of Biopharmaceuticals

, A.S. Rathore and G. Sofer, Eds.) Taylor & Francis (2005) pp 13-30.
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A-Mab: A Case Study in Bioprocess Developmen

t. October 2009, accessed June 5, 2014.
  10.	S. Kozlowski, “Implementation Activities for QbD: FDA Office of Biotechnology Products,” presentation at 2010 WCBP CMC Strategy Forum (Bethesda, MD, 2010).
  11.	L. Zang, X. L. Hronowski, Y. Lyubarskaya, A. Buko, H. Madden, W. Meier, R. Mhatre, “LC-ESI/MS and MALDI-MS for Monitoring of Glycoform-Related Clearance of a Complex Glycoprotein in Cynomolgus Monkeys,” presentation at the 58th ASMS Conference on Mass Spectrometry (Salt Lake City, UT, 2010).


Anurag S. Rathore is a professor at the Department of Chemical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, 110016, India, asrathore@biotechcmz.com; Andrew Weiskopf is director, Technical Development, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142; and Andrew J. Reason is UK business manager, Life Science Services, Group Manager SGS M-Scan Europe.  

Featured Article

Establishing the CQAs of a mAb product by evaluating impact and uncertainty during risk assessment.

Defining Critical Quality Attributes for Monoclonal Antibody Therapeutic Products

The characterization of proteins involves identification of their complex chemical and physical structures and requires the use of a range of analytical techniques. Size exclusion chromatography (SEC) is generally used as a non-denaturing method that provides information on the apparent molecular weight, the presence of aggregates or higher molecular weight (MW) species, and the formation of degradation products, such as protein clips, and impurities. Today, SEC is predominantly used to measure aggregation, because the determination of protein molecular weight by calibrating the retention times against those of known molecular standards is not effective unless the proteins under study have similar conformations and column interactions as those of the standards. The combination of SEC with downstream light scattering analysis and the development of columns that can be used for ultra high-pressure liquid chromatography (UHPLC)-based SEC are overcoming many of the limitations of SEC and enabling more detailed protein characterization.


  SEC is most commonly used to characterize proteins by resolving monomers and aggregates and quantifying them to determine how much of the sample is aggregated, according to Mark Pothecary, product manager of Malvern Instruments’ Viscotek line. “Understanding the aggregate content is important because aggregates not only consume monomers and thus reduce the efficiency of the drug, they also are believed to cause immune responses. Thus, even at low levels, their presence can lead to antibody production against the drug, resulting in more rapid clearance and lower efficacy, and at higher levels, anaphylaxis,” he explains.

In addition, Pothecary says that characterization of oligomers, which are ordered assemblies of multiple proteins, is important because oligomerization controls protein activity. Measurement of molecular weight gives an indication of the oligomeric state.
  
  


  Because SEC is an isocratic method, peak capacity can be an issue, according to Stephan M. Koza, principal applications chemist with Waters Corporation. “Column length can be increased to increase capacity, but a balance is often found between column housing, pressure tolerance, and efficient run times,” he notes. Robert Birdsall, a senior scientist with Waters, adds that the limited dynamic range of SEC often requires the use of columns that span zones of molecular weight ranges. “While this issue is not difficult to overcome, generally a range of SEC columns is required for screening samples, and when working on the extremes of the column (total exclusion for very big proteins vs. total inclusion for very small), resolution is affected much more significantly,” Birdsall observes. 

The range of columns and buffers available for use in SEC, however, means that there are always improvements to be made in method development, according to Pothecary.  “Alternative columns, different buffers, pH, or salt concentrations and in some cases even an organic modifier can all improve performance. Better separation always results in a better characterization,” he asserts.
  Koza and Birdsall also note that SEC is rather insensitive to small changes in apparent MW, and non-specific interactions with the stationary phase can be encountered depending on the column chemistry, which can cause biased results. “In the latter case,” says Koza, “tailing or asymmetry in the chromatographic peaks may be a tell-tale sign, and this problem can often be addressed by increasing ionic strength.” Regardless, they both recommend that orthogonal methods be used to confirm any parameter of interest.

Band broadening between detectors also contributes to loss of resolution and subsequent sensitivity, according to Pothecary. While better connections between the tubing and shorter distances between cells can improve this situation, the best solution in this case is integration of all the detectors into a single unit. “Integration reduces the distances between the detector cells and minimizes temperature variations experienced by the sample, which improves the separation performance, and thus detection and characterization,” he states. 

In addition to resolution, SEC analysis times are also an issue. “At 20 minutes to an hour for a measurement, it is a relatively slow technique,” says Pothecary.


  In certain purification or formulation tasks, it may suffice to determine only the fraction of aggregated protein relative to the unaggregated monomer, rather than the true molecular weights. “In this case,” says Daniel Some, director of marketing and a principal scientist with Wyatt Technology Corporation, “if the monomeric species is resolved from the aggregates and well-behaved in the mobile phase, SEC alone can quantify this fraction.”
  
  


  Most proteins are generally not globular, well-behaved, stable, and hydrophilic like available standards. They also often do not consist of discreet populations, such as monomers and low oligomers or fragments. “Real proteins may be partially or completely disordered, contain significant hydrophobic residues that interact with column packing material in a non-ideal way, or perhaps be continuously heterogeneous as a result of extensive glycosylation or PEGylation with extended conformations vastly different from those of well-folded globular proteins,” states Some. He adds that because SEC separates macromolecules by size, it provides an avenue for downstream characterization by other detectors that do not depend on elution time.


  Downstream characterization by means of multi-angle light scattering (MALS) provides first-principles determination of molar mass through the combined measurement of light scattering intensity and sample concentration, according to Some. In addition, the range of molar mass measured by a good MALS instrument far exceeds that of soluble proteins. Therefore, absolute characterization of the distribution of molar masses, at least those that are resolved by SEC chromatography, is possible. In addition to measuring the absolute molecular weight with light scattering analysis, it is possible to distinguish between monodisperse (i.e., single population) and polydisperse (i.e., poorly separated mixed populations) peaks, giving even greater insight into the exact composition of the sample, according to Pothecary.

Some also notes that for proteins conjugated to a modifier such as glucose, polyethylene glycol (PEG), or surfactant micelles for which no standard SEC reference molecules exist, the combination of MALS with two concentration detectors--usually ultraviolet (UV) and refractive index (RI)--can be used to determine the molar mass of each constituent to assess the oligomeric state and the overall molar mass. “Light scattering analysis with a combined UV and RI detector can provide information on whether the modification occurred and to what extent (i.e., how many PEG molecules are attached). The compositional information can be deconvolved to indicate the percentage of protein and PEG, which when combined with the absolute molecular weight measurement, provides the mass of the complex and its composition, which in turn can be used to determine the number of PEG molecules and the protein oligomeric state,” he explains.

The characterization of membrane proteins is also done in the same vein, according to Pothecary.  “Membrane proteins make up something like 60% of all drug targets, but they have proven difficult to purify and crystallize. Today, however, the same compositional analysis can be done to a purified membrane protein to find out how much detergent it is associated with it and to see if there is any free detergent in the sample, both of which affect crystallization,” he says.

“In addition,” states Some, “certain protein oligomers exist in dynamic equilibrium with monomers or other subunits (‘reversible self-association’) as a function of protein concentration. Since MALS determines the weight-average molar mass at each elution volume, changes in this equilibrium across the chromatographic peak observed as the concentration increases and declines clearly indicate the presence of this phenomenon and can even be used to estimate the equilibrium dissociation constant (Kd).”

If a dynamic light scattering (DLS) detector module is incorporated into the MALS detector, the fluctuation spectrum of light scattered by proteins based on their Brownian motion can be used to determine the diffusion coefficients of the separated components, which can then be related to their effective sizes. “Comparison of molar mass and size is a good indicator of conformation, such as whether the protein is well-folded, denatured, or partially disordered,” Some says.

Greater throughput with smaller particle sizes


  Several evolutionary advances in SEC have had a positive impact in recent years. Smaller flow cells and improved cell design, for example, have made it possible to connect more detectors together without the negative consequences of significant peak broadening and tailing.  “As a result, a single run can generate more and more data, which makes the entire process more efficient,” says Pothecary.

UHPLC, on the other hand, offers a step-change in measurement time, speed, and resolution, but is still a new technology with respect to SEC, according to Pothecary, and its promises still need to be fully realized. In particular, he states that the amplification of peak broadening between detectors is due to the extremely narrow peaks that come from UHPLC. Over the past few years, however, smaller particle sizes have led to greater sample-throughput capabilities for SEC, according to Koza. “Improvements in high-performance liquid chromatography (HPLC)/UHPLC design with respect to system dispersion and sensitivity and advances in particle technology will further improve chromatographic performance in the future,” he notes. 

Some agrees that UHPLC-based SEC has begun emerging in the past few years as the next step in SEC technology for proteins, offering faster separation with better resolution and much reduced consumption of sample and mobile phase. He notes, though, that until 2014, MALS detectors did not keep pace by decreasing the dispersion to match the narrower eluting peaks. The µDAWN MALS detector introduced in March 2014 by Wyatt Technology, along with the Optilab UT-rEX RI detector introduced in 2013, is designed for UHPLC and maintains the ultra-low dispersion required for UHPLC with no loss in sensitivity, according to Some. “In combination with UHPLC UV and IR detectors and an upgraded DLS module, the µDAWN extends all of the capabilities of MALS to the realm of UHPLC,” he remarks


  SEC also has the potential to be combined with other downstream measurements to further enhance protein characterization. The measurement of intrinsic viscosity (IV), for example, gives information on protein density and, therefore, structure. “Non-globular proteins with either elongated or open structures can be readily identified using IV, which then makes size calculation possible. Theoretically, combining measurements of size from DLS and IV can give even more information on shape,” says Pothecary. Some adds that tagging proteins with fluorescent dyes offers the potential for better resolution of protein-protein complexes. “A third-party inline fluorescence detector may be combined with Wyatt’s MALS and RI instruments and software to determine unequivocally the molar masses of such complexes. This ability to combine different detectors is one of the benefits of a modular system as opposed to a fully integrated system,” he says.


Cynthia A. Challener is a contributing editor to BioPharm International.

Light scattering analysis combined with more rapid size exclusion chromatography improves protein characterization.

Analyzing Proteins Using SEC, MALS, and UHPLC

It is well known that Brazil has an immense biodiversity and that the Amazon is the largest tropical rainforest in the world. Traditional Brazilian medicines include African elements, rooted on indigenous groups. Few pharmaceutical companies, however, know at what level phytotherapic drugs are commercialized in the country, how much regulation is imposed for herbal medicines, and if there are any opportunities in this unspoken, mysterious market in Brazil.

Dozens of studies link Brazil’s herbal medicines to successful treatments and cures of various ailments. According to Japanese scientists, there is strong anticancer activity in certain Brazilian traditional medicines (e.g., basic and applied studies for physiological activities of Brazilian traditional medicine). Another study analyzed antifungal properties of plants used in Brazilian traditional medicine against clinically relevant fungal pathogens. One more study made a comparison between ethnopharmacology in traditional Chinese medicine and Brazilian popular phytotherapy.   

One would suppose that due to the potential of the market, there would be dozens of companies investing in the sector. This potential, however, is not translating into market growth, according to industry sources. So why is the herbal drugs market in Brazil almost completely undiscovered and profoundly undeveloped? Is there any real potential for new or existing companies to enter this market? 

There are few figures available on the local herbal drugs market, and its evolution is not officially followed, according to the Brazilian Health Surveillance Agency (Anvisa) . It appears that most of the investment in the Brazilian herbal market has come from the cosmetics sector and not directly from the pharmaceutical industry. 

A December 2011 study conducted by the University of São Paulo concluded that the number of patents filed at the Brazilian patent bank (76 patents) was much lower than that observed in its American (279) and European (328) counterparts and did not show clear signs of growth (1). The study was based on Brazilian, European, and American patent banks, with the objective of evaluating herbal extracts applied in cosmetics.       

Alexandros Botsaris, president of the Brazilian Phytotherapy Association (Abfit), stated in an interview with

 that there are various barriers in Brazil related to registration, environmental legislation, and local production of raw materials, which end up slowing down the availability of quality products in the local market. “Without a proper supply of products, no market is able to grow consistently,” said Botsaris. 

Anvisa has imposed regulation processes that include the registration of herbal medicines, according to Abfit. 

“However, Anvisa was excessively strict regarding safety and efficacy criteria, which caused many smaller laboratories that produced traditional products to shut down,” said Botsaris, adding that was the main reason why the volume of herbal drugs available in the local market reduced significantly in the past 15 years.  

Botsaris adds that another issue is which products should be named “phytotherapic” as the term could include herbal extracts; ‘in natura’ products, or even items sold though network/pyramid marketing. “Brazil’s herbal industry is in a very early stage if compared with other developed countries,” says Botsaris. Brazil tends to follow guidelines published in the US, which could influence the Brazilian herbal market in the long term, he adds. 

Also, according to Botsaris, environmental legislation made the use of Brazilian biodiversity extracts on commercialized products or research more complicated. “The CeGen (Cultural and Genetics Heritage Council) aggressively fined researchers and companies that invested in plants considered of Brazilian heritage, which has greatly inhibited the production of herbal medicines made with Brazilian plants,” said Botsaris. 


According to Ana Cecília Carvalho, phytotherapic coordinator for the Brazilian Health Surveillance Agency (Anvisa), difficulties in the production of herbal remedies may arise due to legislation, which may not be changed by Anvisa. According to Carvalho, there are new norms being edited aiming at meeting other points not foreseen by the Brazilian Law to harmonize the legislation with international standards of quality, safety, and efficacy control.

 “We hope these changes will make it possible for more herbal remedies to be available in the market and [guarantee] that every product will meet current international quality standards,” Carvalho told 

The local legislation for herbal drugs has evolved since 1967 in a few aspects to level itself a little more with international standards. In the past eight years, Brazil expanded its regulation principles regarding raw materials and created its good practice rules and other specific rules for herbal remedies to standardize the sector. 

Since then, Anvisa updated and re-edited rules such as the 

Guideline to Herbal Medicine Registration

 (Director’s Collegiate Resolution [RDC] 14/10) and the 

 (RDC 17/10), among others. “This is the fifth time the Herbal Medicine Registration is being re-edited ... the last version was RDC 14/2010,” said Carvalho

  Alexandros Botsaris, president of the Brazilian Phytotherapy Association, stated the following in an interview with BioPharm International as reasons for growth in the Brazilian herbal drugs market:

According to Carvalho, one of the main changes to the rules is related to the splitting of herbal products into two classes: one that passes all clinical studies needed for the new drugs registration to be granted and another for lower-risks products. “Lower-risk products do not need complete testing,” she said, adding that the data from more than 30 years of usage on human beings is considered. 

According to Carvalho, this makes approval of lower-risk herbal drugs a quicker process, with follow-up control by Anvisa itself. “The legislation update is needed in order to make sure that the consumer understands how the product purchased was registered … if it was through standardized clinical trials or safe and effective usage, which is not clear today,” said Carvalho. 

To re-edit the rules, Anvisa analyzed various points of the international legislation from the World Health Organization (WHO), European Community, Canada, and Australia and extracted “the best” safety, efficacy, and quality principals from each, Carvalho said. According to Anvisa, various associations, scientists, and communities participated in the process. 

Botsaris, however, states that Abfit was not happy with the process. “We have sent various suggestions to Anvisa and never had any idea actually used by them. We currently do not feel any type of proximity with the agency,” he said.  

“Abfit favors legislation and market systems similar to the ones found in Europe, where the government is active in validating traditional products, while there is also more flexibility for registration and prescription of [herbal] products,” Botsaris added. 


  Brazil’s pharmaceutical market has grown in the past years as the volume of products available increased and new products emerged, especially those that were patent-protected, according to Abfit data. The association estimates, however, that the herbal drugs market has not followed the same trend. According to Abfit, the number of new registrations dropped by 50% at Anvisa in the past 14 years.  

 that there has been a reduction in the number of registered herbal drugs from manufacturers. “However, we have no means to offer [comparative] information on whether [the drop] was related with herbal drugs sales or financial values as Anvisa does not follow herbal drug sales and finances [/figures],” said Carvalho. 

Despite the lack of statistics, it is possible to notice that the growth of herbal medicines in Brazil did not follow the evolution of the regular pharma market. On the other hand, according to Botsaris, Brazil historically follows international trends in this sector and the search for natural drugs is increasing locally and worldwide so there are various good reasons to believe that the herbal industry in Brazil will offer great opportunities ahead and should receive more investments in the years to come.


1.	W. Magalhães et al., “Patenting in the Cosmetic Sector: Study of the use of herbal extracts,” 

, 47 (4), University of São Paulo (October/December 2011).   


  Hellen Berger is a business news correspondent based in São Paulo, Brazil.

Global Report

Is there potential for growth in Brazil's phytotherapic drug market?

Brazil's Phytotherapic Drug Market and Regulation

Beginning Jan. 1, 2015, manufacturers and distributors will need to have in place systems able to transmit information on prescription drug movement in the United States from plant, to packagers and various wholesalers and distributors, and ultimately to dispensers. FDA is charged by the Drug Supply Chain Security Act (DSCSA), a key component of the Drug Quality and Security Act (DQSA) of 2013, to issue guidance and rules for establishing such a process and is consulting with all stakeholders on viable approaches and policies (1).

FDA held a public workshop in May 2014 (2) to gain input from manufacturers and other supply-chain parties on developing standards for what eventually will be an interoperable tracking system for prescription drugs. FDA officials and industry leaders further reviewed DSCSA requirements, along with broader supply-chain security issues, at a June conference in Washington, D.C. sponsored by the Parenteral Drug Association (PDA). 

The larger aim of drug tracking is to prevent drug diversion and to keep counterfeit and substandard products out of the US supply chain, observed Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), in opening the FDA workshop (2). Woodcock cited the recent discovery in the US of counterfeit drugs to treat cancer, hypoglycemia, and hormone replacement, and noted the dangers of stolen or diverted products entering the distribution system. Electronic tracking, Woodcock noted, also would help manage product recalls, prevent shortages, and deter criminal elements from introducing substandard drugs into the US market.


  FDA is working with supply-chain parties to tackle its multiple assignments under DSCSA, starting with guidance on how manufacturers and distributors should identify suspect products and then notify other parties that such products are not legitimate. More challenging is a November 2014 deadline for draft guidance that sets standards for interoperable exchange of required information. That includes transaction information (TI), transaction history (TH), and transaction statements (TS)--the “3Ts”--every time a product changes hands. Initially, data will apply to drug lots, as opposed to individual packages, and can be provided via paper or electronic systems. Supply-chain participants have to maintain data records for six years, and they have to be able to provide drug transaction information fairly quickly when requested by FDA or other agencies or is needed to notify trading partners when illegitimate products are detected. By 2017, manufacturers will need unique identifiers on drug packages and electronic data transmission. A fully electronic package-level tracing system is set for 2023, most likely based on the Electronic Product Code Information Services standard. 

There is broad agreement among supply-chain parties that clear standards are crucial to success, but considerable debate about crafting the specifics. Woodcock noted at the FDA workshop that it’s difficult to reach agreement on standards, formats, and practices because that usually requires some parties to change what they’re doing. Workshop participants indicated a need for clearer definitions of basic concepts, such as “efficient interoperability” and “electronic data interchange.” There was discussion about use of packing slips to identify the contents in shipments, which is common practice for manufacturers, but raised objections from wholesalers that reliance on packing slip information would slow down the distribution process. 

There also was debate over using email to send transaction information, an approach that seems simple and direct to some parties, but raises concerns about security and data control for others. Similarly, participants considered whether transmission of a PDF document constitutes dissemination of an electronic or paper document. Electronic transactions that disclose product prices are a concern for manufacturers, who fear that such information could encourage pilferage or theft and undermine rate negotiations. 

Some stakeholders questioned the viability of the envisioned step-wise data transmission system called for by the legislation. An alternative suggestion was for all parties to submit information to a centralized data hub, which could provide records to determine if the product is legitimate when a problem arises, instead of each supply-chain partner passing and accepting thousands of product transaction reports. There also was a proposal that FDA limit its standards to what information has to be transmitted, and leave it to trading partners to figure out how to send data and messages. FDA officials agreed on the need for flexibility but also noted that the legislation requires the agency to issue standards for the program. Overall, stakeholders expressed strong interested in seeing FDA’s policy earlier than November to help them meet the January 2015 implementation deadline.


  While FDA crafts further guidance, manufacturers are preparing for both short-term and long-term changes, which are laid out in a DSCSA implementation timeline prepared by The Pew Charitable Trusts (3). Manufacturers already have spent millions of dollars on technology to implement drug serialization systems and anticipate that it will be costly and challenging to integrate new technologies with existing operations, according to stakeholder perspectives on drug serialization and traceability, prepared for the Pew by Booz Allen Hamilton (4)

Pharmaceutical companies report that off-the-shelf software often is suitable to support databases and communication systems, although customization is needed to meet individual business needs. Most pharma companies plan to outsource systems development and implementation, and a host of IT consultants and vendors have emerged to tackle such projects. 

Despite notable costs associated with serialization and tracking, there is optimism that such initiatives will translate into important gains for the industry. Not only will improved supply-chain visibility help block distribution of counterfeit or compromised pharmaceuticals, there is the potential for added business benefits, according to respondents to the Pew/Booz Allen study (3). In addition to facilitating drug recalls and enhancing cargo security, manufacturers anticipate gaining more timely and accurate production and shipping information. This information could help reduce production lead times, enhance inventory control, process returns more efficiently, prevent distribution of expired goods, help manage supplies for clinical trials, and improve tracking of drug samples. More detailed information on product movement through the supply chain, moreover, could help manufacturers ensure the accuracy of sales and chargebacks and support drug rebate reconciliation. Future gains might extend to improved accuracy in drug-reimbursement systems, better medication adherence by patients, and support for FDA reporting requirements for high-risk products. Alltogether, these developments could support efforts to prevent drug shortages.

As standards emerge for a drug-tracking system in the US, policy makers are looking to facilitate policy harmonization with the European Union, China, and other nations. A broad goal is to agree on barcodes on pharmaceuticals that are acceptable in all markets. European governments are establishing unit-level tracking policies, with requirements for anti-tampering features on packages and guidelines for serialization and authentication. Most countries are adopting two-dimensional barcodes, although China may opt for a linear barcode requirement. Different requirements and implementation timelines in other regions, unfortunately, would add to the complexity of establishing pharmaceutical traceability systems that gain international acceptance.


  1.	J. Wechsler, Pharm. Tech., 38 (4) (2014) p. 14-16.
  2.	FDA, 

 FDA DSCSA Public Workshop Summary-May 8-9, 2014

, accessed June 3, 2014.
  3.	The Pew Charitable Trusts, 

Timeline for the Drug Supply Chain and Security Ac

t, accessed June 1, 2014.
4.	The Pew Charitable Trusts,

 Implementing a Pharmaceutical Serialization and Traceability System in the U.S

 Washington editor, tel. 301.656.4634, jwechsler@advanstar.com. Read Jill’s blogs at

Regulatory Beat

Stakeholders face challenges and benefits from a more secure pharmaceutical supply chain.

Industry Seeks Clearer Standards for Track and Trace

p>The Rx360 pharmaceutical supply chain consortium was launched in 2009 in response to the heparin adulteration crisis, which raised broad concerns about inadequate monitoring of the pharmaceutical supply chain by manufacturers. Since then, Rx360 has attracted more pharmaceutical and biotech companies to support its efforts to enhance supply-chain security. The group has expanded to conduct approximately 25-30 joint audits a year, a collaborative process that can lower audit costs, expand the audit process, and reduce suppler “audit fatigue.” Joint audits coordinate the assessment of a particular supplier of APIs, excipients, container/closure systems, packaging materials, and other raw materials. All sponsors of the joint audit gain access to the resulting report, which then can be purchased by other parties. 

To improve this program, Rx360 established a “strategic partnership” with BSI Supply Chain Solutions to handle joint audit scheduling and management. The goal is to conduct more than 100 joint audits in the coming year, said Martin VanTrieste, senior vice president at Amgen and founding chair of Rx-360. While the audit volume so far is respectable, he believes that there are thousands of suppliers that could benefit from this collaborative program. “But we’re not close to that,” he commented. Not all suppliers have bought in to the joint audit process, he notes, some due to fears the process could damage their relations with customers. VanTrieste also sees a reluctance within leading manufacturers to shift from doing audits themselves. The group’s shared audit program has developed more slowly, but now has more than 200 audits available to members. Drug manufacturers and suppliers tend to feel more proprietary about their own reports on key suppliers, even with the ability to redact confidential information.

Rx-360 has formed an Asia Working Group to develop its program in China, primarily to audit API producers. And it has developed vendor assessment templates to streamline how manufacturers gather information on new suppliers. Supplier audits involve ensuring that these firms have their own security processes to prevent quality problems. The consortium tracks supply-chain policies and provides members with reports on the latest developments, but does not comment on specific rules or policies. A main goal is to identify and support opportunities for regional and international cooperation in addressing pharmaceutical supply chain threats. 

Cover Story

Supplier Audit Program Marks Progress

Human performance or human error prevention, as it is sometimes called, is both a major challenge and a massive opportunity for the biopharmaceutical industry. Human error is a cause attributed to a considerable amount of deviations in the industry and costs the industry significant amounts of time and money. Human error causes batch failures, product recalls, and other product quality and patient safety issues; leads to accidents; and can potentially undermine regulator and investor confidence in both the boardroom and the business. Considering that, on average, a deviation can take 40 person hours simply to investigate and report, the benefits of reducing human errors are easy to see. 

Unfortunately, the typical response to human errors—root cause analysis followed by corrective actions based on tired and worn-out themes, such as “Read and understand the SOP”—rarely succeeds in preventing re-occurrences, or in affecting lasting reform. How, then, can excellence in human performance be achieved? 

This article is the first in a series designed to offer leaders and managers at all levels in the industry a road map to human performance excellence, the hallmark of a high reliability organization. The benefits to be had are many: high-reliability organizations enjoy reduced costs, increased efficiencies, and a competitive edge. Achieving excellence in human performance is a proven, eminently achievable system of cultivating and sustaining exceptional levels of performance. By learning from experts in the field and adapting best practices from industries renowned for human performance prowess, biopharmaceutical organizations can position themselves for excellence in human performance and the industry as a whole. 


  Even the use of complex automation and detailed policies, procedures, and processes can’t change the fact that biopharmaceutical organizations are run by humans, and, like it or not, humans make errors. The very nature of bioprocessing requires a substantial degree of human intervention in the execution of day-to-day operations. Not surprisingly, GMP investigations regularly uncover incidences of human errors. For some organizations, the reported incidence of human error is unacceptably high. Perhaps more damning is when the trend remains largely unchanged over the years, suggesting that, for some, it’s just become the norm and not something that is largely preventable.    

This trend has heightened the concerns of the regulatory agencies, which are pushing for a more formal approach to human error prevention. Industry organizations are increasingly being tasked to “dig deeper” to discover the true causes of human errors. Notice the plural--rarely is there a single root cause and the pursuit of that alone can often blind an investigation and lead to suboptimal corrective or preventative actions.  

Achieving excellence in human performance is an achievable system of cultivating and sustaining exceptional levels of performance.

BioPharm International-07-01-2014

Benefits and Risks of Drug Information on Social Media

Health Systems Raise the Bar on Reimbursing New Drugs

Microbioreactors Increase Productivity

Quantitative Mycoplasma DNA Offers Quality Control

Moving the Needle on Healthcare

Defining Critical Quality Attributes for Monoclonal Antibody Therapeutic Products

Analyzing Proteins Using SEC, MALS, and UHPLC

Brazil's Phytotherapic Drug Market and Regulation

Industry Seeks Clearer Standards for Track and Trace

Supplier Audit Program Marks Progress

Optimizing Human Performance: Part I

Ensuring a Robust Raw-Materials Supply Chain

Challenges in Securing the Biopharma Supply Chain

Biochemistry Analyzers Improve Accuracy

BioPharm International, July 2014 Issue (PDF)