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New Data on the Inspection of Human Cell & Tissue Products by the FDA

A recent report charting inspectional information by the FDA for human cell/tissue therapeutic products shows a marked increase in inspection activity.
The period covered is 2003-2010 and reports an increase in the number of inspections by about 250%, with an average duration of each inspection of 40-45 hours.
During that period, voluntary compliance actions taken by companies as a result of inspections has increased 255% and official action taken has increased 240%. This is against a background of a 260% rise in inspections where no action was indicated.
Interestingly, the most significant increase has occurred between 2009-2010 where there was a 57% jump in inspection activity of these companies by the FDA.
One assumes this is occurring as a result of the exploding interest in cell & tissue therapeutic products and concerns about their relative safety?

Lean Approaches in Bioprocessing to Help Minimize Variability in Production Yields

It’s probably no surprise to many skilled practitioners that one of the major lean initiatives in bioprocessing is to improve throughput and reduce cycle time.
Apparently this is all very obvious but it’s really surprising how many manufacturing operations fall down over this relatively simple concept.
AND this applies equally to both clinical production as well as commercial manufacturing.
Very often there are points of failure in processes that are associated with variability at both the upstream and downstream ends of a process and this is frequently due to poor operational control. As a result, throughput falls due to the failures and extra “belt and braces” measures are often applied to “make sure” that the failures don’t re-occur. This has the effect of increasing the cycle time and reducing productivity.
A better strategy is to take a holistic approach and identify the roots causes and then make appropriate changes to prevent re-occurrence. Simple in concept but often hard in practice!
At the downstream chromatographic separations part of the process there are many areas which introduce variability into a process.
Here we provide some guidance on 7 key areas which are important for a successful Lean bioprocessing strategy.
1. Standardize the packing of the columns using a very tight and monitored procedure. Only use experienced staff to perform this function.
2. Make sure that the system suitability is established and running in a stable mode before running product through the process
3. Establish error proofing measures for the operation of the equipment which should include mistake proofing valving arrangements etc
4. Make sure there is tight procedural control of the preparation of the elution buffers used in the separation process.
5. Establish standardized loading patterns for the columns
6. Establish cleaning and maintenance protocols for the columns and assure that they are followed rigorously.
7. Establish outstanding operator training programs and spend the effort to re-certify staff on a regular basis, especially when campaigning has been suspended for any length of time.

Critical factors in Filing NDC numbers with the FDA

There are three essential factors that need to be considered when deciding whether a new NDC number needs to be filed for a product:
1. Whether the label is different
2. Whether the formulation is different
3. Whether the packaging is different
If any of these three elements changes, then this will trigger the need for new NDC numbering codes for a given product.
Simply put, if the same product formulation is put into several different packaging sizes then this will trigger a new number. If different formulations are put into the same size packaging it will require a new NDC number AND if different formulations are used in the same size packaging this will require a new NDC number.
Clearly if a formulation changes, this will also trigger a new label too, but the point here is to recognize that these individual categories are individual triggers for new numbers and a regulatory filing. Contact us if you need assistance with this process.

Supreme Court Rules that Design-Defect Vaccine Injury Claims are Pre-empted

The Supreme Court ruled on February 22, 2011 that the National Childhood Vaccine Injury Act of 1986 (NCVIA) bars state-law design-defect claims against vaccine manufacturers. The Act had eliminated a manufacturer’s liability for a vaccine’s unavoidable, adverse side effects but was silent on the manufacturer’s liability for a vaccine’s design-defects. The Court stated that the language of the relevant provisions of the act suggested that “the design of the vaccine is a given, not subject to question in the tort action.” In essence, when the FDA licenses the product, and provided that the manufacturer meets regulatory requirements, including GMP manufacture and proper warnings, any design-defects would be insulated from liability.

Issues for Device Combination Products

The development of medical device combination products convenience packages continues to present interesting technical and regulatory issues. Inclusion of pre-sterilized syringes and applicators as part of these products poses problems for manufacturers and distributors due to the opportunity for post sterilization residual contamination and/or plastic leachables/extractables.
Most device convenience kits are ETO sterilized and this can leave ETO residuals on applicators and syringes if they’re included in the paper convenience trays.
If manufacturers are to use these types of devices, then an alternative material of construction may be required to avoid the issues, or alternatively a modified sterilization cycle will be required which assures the removal of the sterilant. As a first step however, testing is needed to quantify the extent of the problem before the right strategy can be developed.

BARDA and their Countermeasures Initiative

Last month was the PHEMCE conference in Washington DC which translated the governments approach to countermeasures production for the next decade or so.
From the discussions it appears that BARDA will be placing a greater focus on CBRN (Chemical, Biological, Radiological & Nuclear) countermeasures issues in the future than it has in the preceding 5 years when there’s been a heavy emphasis on flu related countermeasures, H1N1, for example.
In addressing these issues there would appear to be a number of significant challenges to be addressed including: long term stability/shelf life of countermeasures, platforms for warm based production, platforms for surge production capability and technology solutions to promote efficient product transfer from clinical production to commercial scale manufacturing.
BARDA’s strategy to achieve this will most likely involve a number of public private partnerships and considerable funding investment to support the relevant activities involved.
At the conference, it was estimated that BARDA’s R&D spend would need to be equivalent to a top tier (top 10) pharmaceutical company.

Pharmaceutical Consultants-The Key to a Rapidly Changing Industry

When market conditions, and methods of manufacturing, testing, and technology remain virtually unchanged for long periods, companies within that industry generally manage quite well doing everything in-house. However, when an industry finds itself in the throes of rapid and unexpected change, outside experts are often needed to provide the knowledge and expertise necessary for corporate survival. That is exactly where the pharmaceutical industry is, and why the value of pharmaceutical consultants is becoming undeniable.

In a ten-year-old article titled “Industry Focused: Pharmaceutical Consultancy” (Science, 17 November 2000), Tim Peakman offered some observations that are far more relevant now than they were then. He wrote: “The pharmaceutical industry has undergone radical changes in the last 15 years. It has trimmed the fat and become more efficient, but in the next 2 to 5 years the way it operates is going to alter fundamentally. Change is being driven from all sides, particularly through the impact of new technologies across the whole discovery and development process and from changes in the way that health care is funded and delivered.”

The changes Peakman spoke of have progressed even further, and there are other, more radical changes than those he had in mind in 2000. Growing FDA intrusion and compliance burdens, a dwindling number of blockbuster drugs and looming patent expirations, slowing growth in the market and shrinking profit margins, imminent novel healthcare reforms and increasingly heavy-handed government intervention, rapid technological advances and a growing number of combination products—all these are happening now or are on the horizon. As a result, the role of pharmaceutical consultants is both expanding in scope, as well as narrowing in response to needed specialization.

According to Peakman, in the past pharmaceutical companies mostly used general consultants for large business-wide endeavors like “cost reduction exercises or mergers and acquisitions.” “Today, the pervading beliefs about consultants [that they don't really know much about the pharmaceutical industry or the science involved] are being overtaken by a recognition that using outsiders with specialist knowledge can have its advantages when dealing with the massive changes the industry is facing. Whilst there is still a need for what might be termed generalists in consultancy, more and more consulting organizations are arranging themselves into industry-specialized groups.”

This means that when a drug company turns to a pharmaceutical consulting firm to bolster profitability and hone its competitive edge, the consultants need to have a broad, deep base of knowledge and expertise. Perhaps even more important, good consultants also serve in a sort of “prophetic” capacity of identifying and keeping abreast of developing trends in a rapidly changing industry, preparing companies to adopt pertinent changes so as to remain competitive when the trends are in full swing, thereby applying a type of preventive medicine.

Make no mistake, quality pharmaceutical consultants can be an invaluable asset. From developing a relationship built on mutual trust and respect, to their vast industry specific knowledge and analytical skills, qualified pharmaceutical consultants provide the tools and support that enables their clients to successfully manage costs, improve business performance, and enhance the quality of pharmaceutical products. Consultants can also provide solutions for the manifold certification and approval processes required by the government and other official entities for healthcare products and services.

Smart Consulting Group operates on the understanding that the client-consultant relationship is a partnership that promotes finding the best solutions to achieve the desired business objectives. With Smart Consulting, “you will have access to a team of professional full-time and associate pharmaceutical consultants who possess the expertise to help you in any industry-related challenge.”

Lean Manufacturing and PAT – The Next Level For Pharma

In 2003 the FDA announced the Process Analytical Technology (PAT) initiative to “encourage the voluntary development and implementation of innovative pharmaceutical manufacturing and quality assurance.” This initiative was designed to improve process efficiency of both manufacturing and regulatory phases, and is comprised of four components: data analysis, process analytical tools, process monitoring, and continuous feedback. The quality-by-design aspect of PAT will reduce cycle time thus reducing the wastes of waiting and excess inventory already identified by lean manufacturing.

The early efforts with PAT were focused chiefly on the single aspect of developing and applying analytical tools for timely in-process measurements. However, to fully realize PAT’s goal of complete understanding and control of the manufacturing process, a bigger toolkit must be used. The tools recommended by the FDA are multivariate tools to handle design, information gathering and analysis, process analysis, process control, and continuous improvement. With these tools, pharmaceutical manufacturers can move toward the common goals of reduced cycle times, fewer rejects, increased automation, and continuous improvement in the process that are shared by PAT and lean manufacturing.

The pharmaceutical industry has historically taken a reactive approach to process and quality control – that is, issues were addressed as they arose and not before. Today, however, the industry is moving away from that stance, and toward a quality-by-design approach – an approach that meshes well with the waste reduction, and continual improvement objectives of lean manufacturing. However, the pharmaceutical industry has been slow to take to both the PAT initiative, as well as lean manufacturing solutions, basically for the same reasons. The main obstacle, and probably the hardest to overcome, has to do with cultural issues and mindset. A deeply entrenched attitude of risk aversion in the industry has resulted in a narrow focus on avoiding mistakes, rather than improving processes. Because of this, error-free documentation (largely paper-based) becomes more important than advanced knowledge of the process – a philosophy that is in direct conflict with the risk-based approach and process understanding set forth by PAT.

Another factor is that some companies simply aren’t ready for advanced control from a technological standpoint. Chart recorders – where operators manually record data on paper batch records – are still being used in some plants, and transitioning from this early evolutionary stage to the principles set forth by PAT places an enormous negative impact on a company’s ability to analyze data and control processes, take necessary corrective and preventive measures, and pursue continuous process improvement.

The pharmaceutical industry has been similarly slow in fully adopting lean manufacturing, again, because of culture and mindsets. The highly compartmentalized nature of the industry fosters a manufacturing process composed of many individual parts rather than one continuous, integrated flow. Improving a process that isn’t quite a process yet can be very challenging. Additionally, there’s a reluctance to make the necessary changes – batch size,for instance – when those changes result in the added burden of extensive documentation and testing. As with PAT, the very things that need improvement are preventing companies from taking the necessary steps toward that improvement.

While the principles of the FDA’s PAT initiative share similar goals with lean manufacturing solutions, and are well suited to work in unison, or at least in tandem, there are also similar obstacles preventing their full implementation. However, those obstacles are far less daunting when pharmaceutical consultants and lean manufacturing consultants step in to advise and guide the way.

To learn more about how lean manufacturing strategies can streamline your business and improve your bottom line, visit Smart Lean Manufacturing.

Lean Manufacturing Solves Drug Recalls and Bad Press

In 2009, drug recalls reached an unprecedented high of 1,748. These recalls are attributable, in large part, to outsourcing and indiscriminate cost cutting. Today, more recent drug recalls and the resulting bad press are forcing the pharmaceutical industry to shift their focus to the manufacturing aspect of the drug production process. This latest rash of drug recalls has also intensified both consumer and media backlash against the pharmaceutical industry. A few examples of the most recent incidents:

• 9 October 2010 – Reports of an uncharacteristic odor prompted Pfizer to recall the 40-mg bottles of LIPITOR. (fda.gov)
• 8 October 2010 – FDA pressure led Abbot Laboratories, the manufacturer of Merida (sibutramine), to recall the drug in the US, Canada, and Australia due to the possibility of cardiovascular events after long-term use. (drugrecalls.com)
• 7 October 2010 – FDA violations of its anti-aromatase ingredient resulted in Gaspari Nutrition recalling all lot codes of the testosterone enhancer Novedex XT. (fda.gov)
• 25 September 2010 –Amgen is voluntarily recalling certain lots of EPOGEN and PROCRIT because of possible contamination by glass flakes. (usrecallnews.com)

Coming on the heels of a massive triple recall by Johnson & Johnson, however, these recent events have created a new opportunity for the pharmaceutical industry to emphasize manufacturing and implement much needed lean manufacturing solutions. With the current scarcity of new blockbuster drugs, and the cost of bringing new drugs to market running in the neighborhood of $1.5 billion, drug companies are struggling. The opportunity for them to benefit from a new image and from lean manufacturing implementation is at hand.

Lean manufacturing techniques do work, but effective implementation in the pharmaceutical industry requires knowledge of the special circumstances that exist in the industry, i.e. the difficulties involved in altering batch sizes, the fact that 75% of drug recalls can be attributed to manufacturing defects, the compartmentalized nature of the departments within the process, and burdensome regulatory compliance concerns among others. Further complicating the situation is the growing use of contract manufacturing organization’s (CMOs) which require companies to manage increasingly complex external relationships without compromising quality.

According to Nigel Smart, Managing Partner of Smart Consulting Group, “With so much talk about outsourcing off-shore, American jobs are being lost at an alarming rate in an area where there’s been traditional strength. Strategically, this is a problem for the US Pharmaceutical industry. Perhaps now’s the time for us to re-assert this strength? However, we’ll only be able to do that if we apply the appropriate techniques and methods in a logical and consistent fashion.” Fortunately, manufacturing is the one aspect of drug production most amenable to change and improvement, thereby enabling manufacturers to rebuild their image and reputation. It is also the arena in which lean manufacturing consultants are beginning to play a vital role in the transformation of a struggling industry. Decreased outsourcing combined with implementation of lean manufacturing solutions can help pharmaceutical manufacturers polish up their tarnished image, and regain their competitive edge.

To learn more about how lean manufacturing strategies can streamline your business and improve your bottom line, visit Smart Lean Manufacturing.

Pharmaceutical Consulting and BMI’s 4th Quarter Update

Over the next five years, pharmaceutical consulting could be positioned to play an increasingly critical role, according to the latest estimates from the Business Monitor International’s Pharmaceuticals & Healthcare Business Environment Ratings.

Although the US pharmaceuticals market is currently ranked first both regionally and internationally, projections for the fourth quarter of 2010 and beyond indicate that industry growth is likely to be meager at best. Indeed, the compound annual growth rate (CAGR) is projected to be only 1.76% over the next five years. This slowdown is the result of several factors, including patent expirations, increasing FDA scrutiny, pending healthcare reform, the overall economic climate, and decreased demand for medications and medical services. In this difficult environment, pharmaceutical consultants could prove to be the key factor that enables many drug manufacturers to maintain a competitive edge.

Intimately bound together, the economic climate and healthcare reform strategies will also play a role – one that also opens the door wider for pharmaceutical consulting – in the projected five-year industry slowdown. Real Gross Domestic Product (GDP) is expected to decline from 2.8% in 2010 to 1.8% in 2011, and the weakening economy combined with a dismal labor market has resulted in fewer patients choosing to fill prescriptions, and a decreasing rate of medical services being used by insured people.

Additionally, developments in the third quarter of 2010 will almost certainly result in even heavier compliance and regulatory burdens for drug manufacturers, especially with respect to the OTC segment. The events included the recall of 21 lots of medications – among them certain Tylenol products, as well as Benadryl and Motrin – by Johnson & Johnson. In addition, the FDA recently initiated a new program that will make the safety evaluations for recently approved drugs and vaccines available online. Finally, in August major groups in the consumer, physician, and chemical manufacturing arenas pledged to support a proposed bill intended to protect the US drug supply by allowing the FDA to expand its authority to “safeguard” pharmaceutical supply chains. What this means is that pharmaceutical manufacturers stand to benefit more than ever from the services of knowledgeable pharmaceutical consultants.

Despite everything that is happening, however, the outlook is far from bleak. Pharmaceutical spending in the US was nearly $306 billion in 2009, and the market is expected to reach $334 billion in value at consumer prices by 2014. Still, competition in a market hampered by decreasing growth and a growing presence of state is ever increasing, so ensuring a competitive edge becomes that much more important. Preventive treatment for both patients and the industry is crucial right now.

The best consultants possess the ability and willingness to examine each situation and problem from every perspective then, through analysis and testing, formulate multiple possible solutions. Management and consultants then work together to determine the best solution. Some of the critical areas that pharmaceutical consultants can provide assistance with are:

• Quality and compliance
• Good manufacturing practices (GMP)
• FDA regulatory concerns and adherence
• Laboratory services
• Lean manufacturing
• Training and coaching

Smart Consulting Group is comprised of highly qualified pharmaceutical consultants with extensive industry-specific experience who can guide companies through the upcoming years of slowing market growth, and help them sustain profitability. Their goal is to “provide the competitive edge you need to be the market leader in medical products.”