Can PCMO and PQLI Work in Harmony for Paradigm Change?

PDA has stepped up its efforts to get its training and technical reports more in tune with ICH and a more risk- and science-based industry. These efforts have been underway, says PDA's Rich Levy, but the Paradigm Change in Manufacturing Operations initiative puts them into focus.

PDA has drafted a dossier around four key themes: Life Cycle Approach, Quality Systems, Process Management, and Quality Risk Management, and will use this dossier as the umbrella under which ongoing efforts will be undertaken.

In this article from my recent discussion with Levy, he goes out of his way to emphasize that PCMO is intended to complement, not counter, PQLI efforts already underway at ISPE.

--Paul Thomas

ADAPT Agenda Set; Throckmorton to Speak

The final agenda is available for September's ADAPT (Accelerating Development and Advancing Personalized Therapy) congress in Washington, D.C.

A quick summary of the tracks:

Track 1: Optimizing Clinical Trials
Track 2: Implementing Personalized Medicine
Track 3: Advancing Cancer Therapy
Track 4: Bridging Silos in Biomarker Development

Featured speakers include FDA Deputy Director Douglas Throckmorton; J. Carl Barrett, VP, Global Head Oncology Translational
Medicine, Novartis; Nicholas C. Dracopoli, VP, Biomarkers, Centocor R&D, Johnson & Johnson; and Giora Feuerstein, AVP, Head,Discovery Translational Medicine, Wyeth Research.

--Paul Thomas

QbD Presentations on Parade: DynoChem's User Meeting

DynoChem has made available presentations from its user group this past May. Registration is required to access the content, but among the materials available are:

Roles of Mechanistic and Empirical Modeling/DOE in Achieving Quality by Design, by Paul Stonestreet of GSK

Practical Insight on New Model Development: Filtration and Centrifugation, by Rich Ballenger of Abbott

Process Modeling Based Approach Towards Quality by Design for an API Synthetic Step, by Shawn Brueggemeier, Emily Reiff, Olav Lyngberg, Lindsay Hobson, and Jose Tabora, BMS

Practical Aspects of Distillation Modeling in DynoChem, by Carolyn Cummings of Amgen

An Example from GSK's Design for Manufacture Initiative: Use of Dynochem in Conjunction with Lab and Pilot Scale Data to Advance Process Understanding, by Dharmesh Bhanushali of GSK

How Process Safety and Environmental Lab Can Guide Process Development, by Viviane Massonneau of Merck

Lean and Green: The Value of API Process Design, by David am Ende, Pfizer

--Paul Thomas

How Varian Complements Agilent for QbD

Agilent's purchase of Varian should give the company much more prominence in the QbD space. As Investor's Business Daily put it, "Varian's products are used to help design new therapeutic drugs, while Agilent's products help analyze the causes and cures for diseases."

Here are a couple white papers out from Agilent this year:

Using Design of Experiments for HPLC Method Development

Using Fiber Optics to Speed and Simplify Formulation and Method Development

--Paul Thomas

QbD for Biopharma: New Course at PDA FDA Joint Conference

This year's PDA FDA Joint Regulatory Conference in D.C. in mid-September has an excellent program top to bottom. (Here's the agenda.) It will also feature a new course by Anurag Rathore (see yesterday's post on his new book) on QbD for Biopharma.

Rathore has just posted the tentative outline for the course on our LinkedIn group. If you're not a LinkedIn member, here is his overview--comments are welcome as the program is finalized.

Critical Quality Attributes (Patrick Swann): Potential CQAs for Mabs; Biological Activity Matrix; Product-related variants; Characterization of variants and setting limits (ICH Q5E); Clinical pharmacology studies; Specifications (ICH Q6B); Biological characterization

Design Space (Anurag Rathore): Clinical design space; Product design space; Process design space; Case Study I – Establishing process design space for a Pichia fermentation product; Scale down modeling; Failure Mode and Effects Analysis (FMEA); Design of Experiments (DOE); Parameter-parameter interactions; Worst case studies

Group work I (All): Group discussion to identify and list gaps attendees see with respect to molecules under commercialization at present and also legacy products.

Risk Assessment and Management (Patrick Swann): Review of historical approaches; ICH Q9 guidance; Quality risk management process; FMEA

Regulatory Aspects (Patrick Swann): OBP QbD pilot program; Observations based on review of proposals for categorizing quality attributes

Establishing Control Strategy and Lifecycle Management of Design Space (Anurag Rathore): Creating control strategy; Process validation; Filing; Process monitoring; Raw material management; Process analytical technology (PAT); Case Stud II – Multivariate analysis for a mammalian cell culture step

Group work II (All): Group discussion of gaps identified earlier

Wiley Publishes QbD for Biopharma, Edited by Rathore and Mhatre

Wiley and Sons has published the 288-page "Quality by Design for Biopharmaceuticals: Principles and Case Studies," edited by two of biopharma-QbD's leading advocates, Anurag Rathore and Rohin Mhatre.

Expect the book to become one of the definitive resources for QbD, given the impressive list of contributors. For those who don't have the $125 for the cover price right now, the Introductory Chapter by the editors may suffice; it's available here (scroll down to "Product Samples"). It's an excellent overview of basic QbD concepts such as CQA's, Design Space, raw materials and their impact on QbD, and PAT.

--Paul Thomas

What Is the Real Meaning of Pharma Innovation?

Britain’s NICE (National Institute for Health and Clinical Excellence) is charged with providing guidance on promoting good health among citizens of the U.K. Unfortunately, NICE has had a contentious relationship with the drug industry in general, and has often been viewed not as a promoter of public health but rather an impediment to innovation which might benefit the public. One way to put it: “Pharma sees NICE as a barrier to its ambitions to bring products to patients. NICE sees itself as the guardian of the public purse and of all patients.”

The above statement is from Sir Ian Kennedy, who was hired by NICE earlier this year to review the organization’s procedures and make recommendations for how it might turn things around—i.e., “make nice” with pharma while still protecting the public interest. Kennedy has issued his final report, "Appraising the Value of Innnovation and Other Benefits," with a laundry list of recommendations for NICE. But, for those of us outside the U.K., we might find most compelling Kennedy’s ruminations on the meaning of innovation within a pharma context. Here are some of those thoughts, from the report:

“ . . . It will come as no surprise that, while everyone was content to use the word [innovation], and everyone agreed that it was a good thing, it was not easy to identify what was being discussed. In fact, as is common in policy-making, the absence of any hard centre of meaning allows people from all quarters to appear to be in agreement, without the need to nail down what it is that they were agreed on.

4.8 There is no shortage of definitions of innovation. Their very number suggests an amorphous concept. It is clear to me that the notion of innovation has a range of connotations which are, to a degree, context-specific. And, the world of pharmaceutical products is one such context. As a first step, it may help to know what Sir David Cooksey had in mind when he called for this study. When I spoke to him he referred to innovation as connoting “different ways of doing things which bring improved outcomes”. This helps. There is the idea of difference, or newness, and the idea that it represents an improvement on what went before. . . . it should be clear that something more than newness (or difference) plus some degree of improvement in effectiveness may be necessary to qualify as innovation in this specific context. . . .

4.10 Where innovation becomes important, therefore, is when Pharma states that a product meets three initial criteria, in that the product: But, they will not warrant any special treatment. Only if they are priced in a way that meets NICE’s established approach, will they warrant approval. Such products may be described as innovative, but the claim alone will cut no ice, nor bring any special treatment.
• is new
• constitutes an improvement on existing products
• offers something more: a step-change in terms of outcomes for patients

Kennedy agrees that “step-change” is in itself amorphous as well, but this is what we should by striving for as an industry, and this is the concept around which NICE and pharmaceutical companies can coalesce to expedite products to market that are truly “innovative.”

--Paul Thomas

Snooping Around: A Peek at Quality Management at Sanofi

Found on the blogosphere is this summary of Sanofi Aventis' take on Quality Management, from one of its teams in Union, N.J. The recommendations at the bottom of the posting are the most intriguing, and suggesting that manufacturing may be underappreciated and QbD underutilized:

Sanofi-aventis is still struggling with on-time delivery. Management mainly sees manufacturing as a cost center. About 40% of the plant equipment is over 10 years old and some are manually operated. Elements in the operational excellence toolkit, such as Quality by Design, Process Analytical Technology and advanced process control are being underutilized. Models are not yet flexible enough to adjust production capacities based on demand. In addition, regulatory compliance and plant safety were lower this year. . . . If Sanofi-aventis wants to increase the benefits of quality, company leadership must make operational excellence a priority.

--Paul Thomas

H1N1 Puts Onus on Industry to Embrace QbD and FDA's Risk-based Dream

If ever there were a time for the industry to embrace QbD, it is now, as the threat of an expanding H1N1 pandemic looms and manufacturers scramble to develop and manufacture significant volumes of vaccines to counter the spread of the virus. In this his latest article (also published in the July/August issue of Pharmaceutical Manufacturing), Pharmatech's Bikash Chatterjee puts the threat in perspective (looking back towards the bird flu and even Spanish flu of 1918), and makes an impassioned case for the adoption of Q8 and Q9 principles as a means of accelerating development and helping to reduce or even extinguish the danger that H1N1 presents.

He concludes:

For an industry that has had its fair share of bad press in the last few years over public safety concerns, this is our chance to step up to the plate and show we can deliver when we need to. If we fail, the FDA can look to another long, slow transition as it struggles to enforce its new policies on risk-based process development and quality assurance.

--Paul Thomas

Can QbD Help Build Better Partnerships?

As far as I know, no one has looked into how to apply Quality by Design to outsourcing situations more than Russ Somma, president of SommaTech consulting. Russ has published on the topic in the past, and was the lead speaker on our recent webcast on outsourcing excellence (available on-demand here and also featuring Rakesh Kishan of UMS Advisory and Ron Perry of Wyeth Consumer Healthcare).

Here is the printed summary of Russ's webcast presentation. His underlying premise: "QbD does not become the driving factor of partnerships, but it becomes the philosophy against which one sets up strong partnerships."

Also, here is a related article by Russ and colleague Andy Signore from Contract Pharma last year.

--Paul Thomas

Risk Management Strategies for Extractables and Leachables

FDA's Ingrid Markovic has just published in American Pharmaceutical Review on risk management for extractables and leachables. Here's a link (subscription required), and here is the abstract:

Extractables and leachables (E&L) are chemical entities, which can be released into intermediate material or final therapeutic biologic protein product at various times during upstream and/ or downstream manufacturing steps, packaging operations and/or storage. These substances may pose a safety risk to the patient by causing toxicity, carcinogenicity, immunogenicity and/or endocrine dysregulation. They may also alter product physico-chemical properties via direct interaction with the active pharmaceutical ingredient or, indirectly, by interacting with the excipients in product vehicle, thereby adversely affecting the product quality. Current paper will address a risk-based approach to conceptualizing, evaluating and executing identification and characterization of E&L along with regulatory considerations regarding the impact of these impurities on product quality, patient safety and clinical efficacy. Selected case studies are presented and discussed.

The QbD/Six Sigma Connection, Revisited

I had a good talk a few weeks back with Patheon CEO Wes Wheeler about initiatives he's undertaken to increase performance across all sites, and to use performance indicators to drive marketing for new business. (Article here.) I also e-communicated with Patheon executive VP and CTO Paul Garofolo about the company's Patheon Advantage Lean Six Sigma and its ongoing progress. You can read that Q&A here, but I thought Garofolo's take on the QbD/Six Sigma overlap helpful:

PhM: Where is Patheon in terms of adhering to FDA’s vision of Quality by Design, and what role does QbD play in the PA program?

P.G.: We’re making great progress. It’s all about culture change, on both fronts. The fundamentals of Lean Six Sigma support the fundamentals of QbD. Some tools, particularly Quality Function Deployment, Design for Six Sigma and Design of Experiments are particularly well-matched with QbD. We’re finding that the methods we’re developing and the culture change we’re building with PA support fully our move to QbD.

--Paul Thomas

Mulling Adaptive Clinical Trial Design, and Hula Hoops

Can accumulating clinical trial data be used to adapt trials in their earlier stages to either optimize them or suggest that they ought to be terminated? That's the premise of adaptive clinical design; this article from Applied Clinical Trials ponders the question of whether adaptive trials are here to stay or will go the route of the hula hoop.

Thanks to the Agile Clinical Development blog from Health Decisions for passing this one along.

--Paul Thomas

Biosensors in Clinical Trials: More from John Lowry in Ireland

I blogged a few weeks ago about the potential of biosensors to be used to monitor neurochemical brain activities in clinical trial patients in real time, from the work of Irish researcher John Lowry. Yesterday, I spoke with Lowry to dig further into why companies like Lilly are interested in his technology, and what obstacles exist before biosensors might be used in human trial subjects. Here is the summary of that interview.

--Paul Thomas

QbD in a Nutshell

A good, succinct overview from today's Pharma Compliance Blog of QbD's past and where it stands today, from Gary Miller of CIS Partners.

--Paul Thomas

White Paper: Operational Efficiency in Clinical Trial Management

Good reading: A multi-article white paper from Oracle, including Accenture’s Henry Levy on enabling technology, Genzyme’s Jennifer Hunt on implementing a trial management system, and several leading consultants on clinical trials management of the future. While the paper promotes clinical trial management systems such as Oracle’s Siebel offering, it’s a strong overview of the current data management climate in general.

--Paul Thomas

Innovation: Are You in a Dynamic Ocean or Shrinking Pool?

Where will the innovation of the next century take place? McKinsey and Co. has put together an interactive innovation heat map which gauges global hotspots based on their size, diversiy, and momentum, as a means of estimating where future innovation will reside.

Click continue at the bottom of the landing page to view.

--Paul Thomas

On the Horizon: Drug Discovery and Development Week

Drug Discovery and Development Week, a collection of five conference themes around one exhibition, is slated for the first week of August in Boston. Among the highlights: In the Drug Safety Strategies to De-Risk Compounds event, William Mattes, former director of toxicology for the Critical Path Institute, will deliver a keynote on Skirting Drug Safety Potholes in the Critical Path to POC, while FDA senior scientific advisor Wendy Sanhai will discuss Biomarker Development and Clinical Qualification. The Cancer Drug Development track will feature a debate on the effectiveness of current methods of development via cancer stem cells. There's plenty more on hand, of course, including a keynote by Daiichi Sankyo president and CEO Takashi Shoda, on the challenges of building a global drug company in today's market.

--Paul Thomas

How QbD Can Leverage Outsourcing Partnerships

Forgive the self-promotion, but today I've been reviewing our recent webcast on Operational Excellence for Building Better Partnerships, and think it's a fantastic overview of how Quality by Design and principles of operational excellence can be applied to pharmaceutical contract relationships, for the betterment of everybody involved. In particular, consultant Russ Somma discusses how challenging QbD concepts such as Design Space can be simplified and applied to outsourcing relationships, and the ideals of QbD can be shared with partners. Consultant Rakesh Kishan gives a good talk on keeping core employees in mind in all outsourcing situations, and Ron Perry of Wyeth Consumer Healthcare details his company's innovative supplier quality excellence program.

The webcast is free; registration is required.

--Paul Thomas

Pharmaceutical Allies: QbD and Six Sigma

A rather lengthy but good PowerPoint presentation from an ISPE breakfast seminar on the link between QbD and Design for Six Sigma, courtesy of consultant Murray Adams.

--Paul Thomas

Quality Risk Management in Jersey

Roche and Dyadem have put together a program on Quality Risk Management for the end of this month in Princeton, N.J. Dyadem's offerings are well positioned for the QbD movement . . . should be an interesting program.

--Paul Thomas

Progressive Collaborations: GSK Gets First Contributor to Patent Pool

Another exciting collaboration speeding development: Alnylam has become the first company to jump into the patent pool that GSK has established to aid development of drugs to confront tropical diseases. Alnylam will contribute some 1,500 current and pending patents, tripling the number that GSK has already contributed itself.

GSK CEO Andrew Witty: “The key objective of the pool is to make it easier for researchers across the world to access intellectual property that may be useful in the search for new medicines to treat neglected tropical diseases. The more companies, academic institutions and foundations that join the pool, the more effective it will be. Alnylam’s announcement today is therefore a welcome and significant step forward.”

--Paul Thomas

Public and Private: Janssen Alliance for TB Drug Development May Serve as Model

An interesting note from a few weeks ago on an agreement between Janssen subsidiary Tibotec and the not-for-profit TB Alliance to share resources and expertise. Says the alliance's president and CEO Mel Spigelman, “Since the TB Alliance was founded, we have assembled the largest pipeline of new TB drugs in history . . . " It's a great model for collaboration, cost sharing, and bringing needed drugs to market that otherwise would not have gotten the full resources and backing they deserve.

--Paul Thomas

Real-Time Neurochemical Monitoring of Trial Patients?

A good article in the Irish Times detailing some of the work in the Emerald Isle to speed drug development. The lead is about the work of John Lowry at the National University of Ireland Maynooth. Some of Lowry's research is available online. Here is a journal article detailing his team's efforts to enhance the selectivity of its biosensors. And here is a thorough video on Lowry and his biosensor work.

--Paul Thomas

Microsoft's Les Jordan on DIA 2009

Microsoft's IT Life Sciences specialist Les Jordan offers up a nice summary of his experience at DIA last week, including photos and (for romantics) a shot of the San Diego sunset.

--Paul Thomas

Blue Reference's Van Eikeren Outlines QbD and Other Strategies

A good interview with Blue Reference's Paul Van Eikeren regarding the company's strategy, including a brief mention of its consortium with big pharma companies to develop a QbD enterprise solution based upon its Inference for R platform. (Here is the press release on that consortium from a while back.)

--Paul Thomas