The Q11 guideline will be folded into the Quality trio which includes ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System, which together detail quality-by-design (QbD) concepts for pharmaceutical development and manufacturing. Although the ICH Quality trio guidelines apply to drug substance as well as drug product, industry and regulators felt there was a need to clarify QbD or “enhanced” concepts for drug-substance manufacture.

“There are fundamental scientific differences in the process for drug-substance manufacture and the process for drug-product manufacture, including impurity control and removal and chemical transformations,” explained Pharmaceutical Research and Manufacturers Association (PhRMA) representatives of the ICH Q11 expert working group to PharmTech. These representatives, among others, talked to PharmTech earlier this year regarding the expected approval of Q11; their discussion of the guideline can be found in the February 2012 issue cover story.

Q11 describes approaches to developing process and drug substance understanding and also provides recommendations to industry on what information should be provided in Common Technical Document sections 3.2.S.2.2 – 3.2.S.2.6. The guideline provides further clarification on the principles and concepts described in ICH Q8, Q9, and Q10 as well.

Read the full ICH Q11 guideline

Read recent PharmTech cover story on ICH Q11

Read related blog

PharmTech discusses this issue and related compliance issues in a recent webcast, available on-demand here.

Single-cell genomics holds much potential for more targeted drug discovery through a better understanding of cells and their interactions. Heterogeneity exists among cells in tissue samples and other populations, but this cellular variability is masked by averaging data across pooled cell samples. The ability to tease out single-cell genomic data has historically been limited by a lack of standardized, user-friendly methods that would allow the study of individual cellular variability at high definition, high throughput, and low cost, according to a Fluidigm press statement. Advances in technology, such as microfluidic chips and high-throughput instruments, have made single-cell studies feasible by converting cellular heterogeneity from a source of background noise to a source of information to enable discoveries.

According to Fluidigm, the company’s technology provides the capabilities required to analyze single cells, namely microfluidics and sensitivity at the nanoscale level, parallel processing of a large number of cells, and interrogation of a large number of gene targets. The center will be housed at the Broad Institute in Cambridge, Massachusetts, and will feature Fluidigm single-cell tools, protocols, and technologies. The center intends to develop novel single-cell, microfluidic approaches for gene-expression profiling, RNA/DNA sequencing ,and epigenetic analysis. The goal of these efforts is to make single-cell research accessible to the greater scientific community by developing and disseminating new workflows, reagents, bioinformatics tools, and data sets.

It is hoped that these advances will provide the tools for better understanding the underlying causes of many diseases, including the progression of individual cancers, differential immune responses, and the maturation of stem cells. Targeted genomic information is key to understanding disease states for developing better therapies, an important ongoing need in current and future drug discovery.

More than a year has passed since the FDA issued its guidance, “Process Validation: General  Principles and Practices,” which describes process validation in three stages – Process Design, Process Qualification and Continued Process Verification. Companies are making progress with how to incorporate these guidelines cost effectively for science-based decision making that improves quality–the consequences of poor quality are too costly.

The guideline for Stage 3 – Continued Process Verification – states, “An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e))…The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.”

In reality, manufacturers have to balance available resources (i.e., “trained personnel”) with tasks such as accessing and aggregating data from multiple sources, including paper records. This can be especially challenging without proper IT systems in place to effectively manage process validation data throughout the tech transfer and manufacturing process.  When evaluating technology options, manufacturing teams should look for tools that can help them more easily monitor product and process data as outlined by the FDA.

Companies that adopt QbD and implement best practices for data analysis to achieve a culture of process understanding will reap greater rewards, including:

• Improved batch yields
• Lower final product testing and release costs and reduced operating costs from fewer deviations and investigations
• Reduced raw material and finished product inventory costs
• Faster tech transfer and regulatory approval of new products and process changes
• Fewer and shorter regulatory inspections of manufacturing sites.

A handful of these drugs are being pulled from the shelves and given a second chance in a new initiative announced earlier this month. NIH’s new National Center for Advancing Translational Sciences (NCATS) is partnering with Pfizer, AstraZeneca, and Eli Lilly, which have agreed to make select compounds available for a pilot initiative to test promising compounds for new indications.

A total of $20 million will be used from NCATS’ budget to fund the initiative. Scientists may apply for research grants of up to three years duration for preclinical and clinical feasibility. Industry partners will supply around 20 compounds to participating researchers, as well as access to related data. The program also incorporates template agreements designed to streamline the legal and administrative process for participation, and a framework for handling intellectual property used or developed within the program.

In times of shrinking pharma R&D budgets, this is just the type of project by which industry can capitalize on relationships with academia. In the release, Jan Lundberg, PhD, executive vice-president, science and technology, and president, Lilly Research Laboratories, sums it up. “Discovering and developing new medicines, regardless of the therapeutic area being studied, is a complex and expensive process and we look forward to collaborating with the NIH and academia for the benefit of the patients we all serve.”

Hand-held instruments containing the libraries are being used at the borders to rapidly verify and authenticate materials via XRF, IMS, Raman, and NIR screening methods. Materials in question are then investigated at local FDA laboratories.

FDA has been collecting samples from the industry to add to the library but only has about 20% of its most wanted materials (see Table I in the July 2011 PharmTech article) thus far. Incoming materials must match a Hit Quality Index of 0.95. Bushe pointed out that the supplier or site of material used for the library has not had a significant or statistical impact on the library index to date. Samples are therefore being collected from various industry players and from various sites.

Looking ahead, FDA aims to fill its library with all the excipient samples it’s seeking and will work to finalize its classification and modeling strategies.

In the UK, the National Health System (NHS) has taken the controversial step of cutting the cost of treating wet age-related macular degeneration (AMD) by prescribing a cheaper drug over a more expensive one. The controversial element? The cheaper drug isn’t licensed for wet AMD.

Scandalous isn’t it? Or is it?

The approved treatment for AMD is Lucentis (Ranibzumab), which is marketed by Genetech (now owned by Roche) in the US and by Novartis elsewhere. The drug costs around £740, but has been approved by the UK’s cost–effectiveness evaluation agency, NICE.

But according to the NHS, Roche’s Avastin (bevacizumab) is just as effective and costs significantly less — around £50. The UK’s National Institute for Health Research Health Technology Assessment has even funded a study examining the two drugs. The results, released last week, show that both treatments are equally effective in wet AMD. In addition, it was found that using Avastin in place of Lucentis could save the NHS £84.5 million annually. A similar study has also been conducted in the US, with both drugs being shown as effective.

Novartis has hit back, claiming that the results highlight “serious safety concerns” and a “significantly higher risk of serious systemic adverse events” with Avastin versus Lucentis.

But the US study added, “Although Avastin had a higher rate of serious adverse events, they were distributed across many different conditions, most of which were not associated with Avastin… The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study.”

Novartis feels so strongly about the situation that it is taking the case to court by seeking a judicial review of the decision to enable patients to choose between Lucentis and Avastin in the UK. The Association of the British Pharmaceutical Industry is reportedly backing Novartis after speaking out at the association’s recent annual conference in London. The backing is based on the fact that NICE has approved the use of Lucentis so it should be made available, as well as the fact that Avastin is unlicensed for treating wet AMD.

Another option is for Roche to seek a license for the use of Avastin in wet-AMD, according to NICE Roche has said that it is not interested in pursuing this. There’s a good reason for this too. Both Lucentis and Avastin were both developed by Genetech, which Roche acquired in 2009. The drugs are similar in that they both act against Vascular Endothelial Growth Factor, but were developed with different specifications. In particular, Lucentis is designed specifically to be injected into the eye. From a cost point of view, why would any pharmaceutical company want to license Avastin for wet AMD when more money can be made from Lucentis? A lot of work also went into developing Lucentis specifically for eye conditions. Pharmaceutical companies are businesses after all and profits have to be a consideration.

Doctors in both Europe and the US have been using Avastin off label for years for wet AMD. It will be interesting to see if anything changes as the situation with the NHS and Novartis unfolds.

Late last month, the Senate Health, Education, Labor and Pensions (HELP) Committee approved the Food and Drug Administration Safety and Innovation Act. The bill, which now goes to the full Senate for approval, reauthorizes the FDA user-fee program and also contains measures to strengthen ways to deal with drug shortages. The bill proposes revising the timing of advance notifications of possible shortages, requiring a strategic plan on shortages, broadening the definition of what constitutes a meaningful disruption of drug supplies, and creating a process for physicians and others to report evidence of shortages, as outlined by the American Medical Association (AMA) in analyzing the bill. Industry groups, such as AMA and the American Society for Health-System Pharmacists, support these measures.

In a blog and in testimony before the Subcommittee on Health of the House Committee on Energy and Commerce, which also is considering  measures to address drug shortages, FDA Commissoner Margaret Hamburg outlined the progress made in reducing drug shortages. Last October, President Barack Obama issued an Executive Order that directed FDA and the Department of Justice to take action to reduce and prevent drug shortages. Since the issuance of the Executive Order, FDA has successfully prevented 118 drug shortages and reduced the number of drug shortages. According to Hamburg’s blog, 42 new drugs in shortage have occurred in 2012 thus far compared to 90 new drugs in shortage in a comparable time period last year.

In her testimony, Hamburg outlined FDA efforts. When it learns of a potential shortage situation, the agency works directly with the affected manufacturer in several ways: developing temporary workaround solutions to manufacturing or quality issues; consulting with the manufacturer to resolve the underlying problem; or helping the manufacturer find additional sources of raw materials. It also expedites the review of submissions by the manufacturer that may alleviate the drug shortage while continuing to meet safety standards, which may include requests to extend the expiration date of products, make manufacturing changes to increase capacity, use a new raw material source, or change product specifications. FDA can also use its regulatory discretion for a manufacturer to continue marketing a medically necessary drug if the manufacturer can develop a method to resolve a quality issue prior to the drug’s administration. In addition to working with the affected manufacturer, FDA also does the following: works with third parties to determine whether they can help avoid or minimize the shortage; expedite reviews of generic applications for products facing potential shortages; and in certain situations, when a shortage cannot be resolved immediately, FDA can use its regulatory discretion for the temporary import of non-FDA-approved versions of critical drugs after ensuring there are no significant safety or efficacy risks for US patients.

These measures have had impact, but a question is whether more systematic means should be in play. Some commentary on this subject have suggested national stockpiles, such as those used for vaccines, be used to avert shortages. Whether this is an appropriate solution is unclear. What is clear, however, is that strengthening regulatory oversight to prevent or reduce drug shortages is an important goal for industry and consumers alike.

It is clear that the industry is moving toward a new model in pharmaceutical manufacturing, a science- and risk-based approach under a product life-cycle concept as many of the conference sessions reflected. Driven by quality-by-design principles, companies are seeking ways to enhance their process understanding and build better control strategies based on that understanding in their manufacturing processes. Strategies for risk assessment and risk mitigation have been an important theme among the conference sessions as well as the tools, such as process analytical technology (PAT), which can be used to better that understanding. Related to these efforts is a focus on FDA’s  recent process validation guidance, also a subject of several conference sessions. The guidance aligns process validation activities with a product life-cycle concept and with existing FDA guidance and ICH  guidelines, such as Q8 (R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System as a means to encourage the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process life cycle.

As much as regulatory considerations and the overall goal of product quality shape manufacturing processes, there also are market considerations. As pharmaceutical companies continue to align their manufacturing networks with product demand, decisions on how to best manage capital and operating costs emerge. In certain areas, such as biopharmaceutical production, a prevalent theme among the conference sessions and in the product innovation of exhibitors is the adoption of single-use components and technology to afford greater manufacturing flexibility as a means to reduce capital expenses as well as operating costs, such as by facilitating turnaround times between product campaigns and reducing set-up times. Modular manufacturing is the further iteration of this paradigm, and although still a niche area, several exhibitors emphasized these approaches in bioprocessing and fill–finish operations.

So as much as the new products and product enhancements are the stars of Interphex, they reflect the underlying themes for the new paradigm for pharmaceutical manufacturing: one based on deeper process knowledge and understanding using a science and risk-based approach to manufacturing that can meet the always foremost goal of  product quality.

Will this fly? It’s hard to imagine, given the precedents set by the generic drug approval pathway, and the reality of how FDA approves drugs. But it reads as a shot across the bow to those coming along behind with biosimilar versions of Abbott’s products. Be prepared to discuss the matter further in court.