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The FDA Interview: Is pharma getting worse at manufacturing?

Published on 29/09/10 at 08:00am
Phil Taylor
FDA director of manufacturing and product quality Rich Friedman
Rick Friedman, director of manufacturing and product quality division at the FDA’s Center for Drug Evaluation and Research

It seems that barely a week goes by at the moment without news of another pharmaceutical company falling foul of the US Food and Drug Administration’s regulations on Good Manufacturing Practice (GMP).

In the last 12 months alone there have been high-profile product contamination incidents, product recalls and facility shutdowns involving some of the biggest names in the industry, including Johnson & Johnson, Procter & Gamble, Genzyme, Teva Pharmaceuticals and Ranbaxy.

But this newsflow does not indicate a marked trend towards laxer standards in pharmaceutical manufacturing, according to Rick Friedman, director of the manufacturing and product quality division at the FDA’s Center for Drug Evaluation and Research (CDER).

“There has been an uptick in the number of warning letters for GMP violations sent out over the last year, especially in the foreign arena where the number sent out tripled between 2008 and 2009,” said Friedman.

“These have generated a lot of publicity, but this does not mean that drug quality on the whole has decreased,” he added.

A look at the number of warning letters associated with GMP transgressions (see table, right page) would indicate some increase in activity warranting enforcement action, though hardly an explosion in cases. Similarly, while there have been spikes in recalls of products, these are more often than not attributable to one particular incident, for example in 2007 when a single medicine repackager recalled almost every single product line.

The rise in the number of warning letters can be attributed to three main factors, according to Friedman. The first is the frequency of inspections; although the number of domestic facility inspections has remained flat or even trended downward year by year over the last decade, inspections of overseas plants have increased.

The second and related factor is a shift towards a risk-based inspection plan in which the goal is to select sites which have the most process, facility and/or product risk associated with them.

“FDA’s programme has traditionally been driven by pre-approval inspections for foreign plants, but it now better targets higher risk facilities. This includes facilities that may not have been inspected for several years,” said Friedman.

The aim is to pick up those plants that may have fallen out of compliance since the pre-approval or other FDA inspectional visit, with a particular emphasis on sites in countries with developing regulatory systems that may not be as rigorous as those operating in the USA or EU. The third factor is faster, more assertive communication of sanctions where major deficiencies are encountered, according to Friedman.

“In the past we frankly took a little longer than would be ideal in getting our advisory actions out to firms,” he said. “The threshold for issuing a warning letter has not however changed. What has changed is the swiftness in which we send them out and the effect of our risk-based inspection programme.”

“The inspectional programme is finding problems earlier than in the past and, in some notable cases, have identified quality lapses at firms that increase the potential for putting the consumer at risk.”

So does this better inspection programme mean that business as usual in the industry can be sustained, and there is nothing to worry about? Not at all, according to Friedman, who noted that the FDA is becoming increasingly concerned about the ability of senior management in pharmaceutical companies to maintain tight control of manufacturing, given the current industry-wide drive towards reducing costs.

That in turn is creating a shift towards outsourcing of production and increasing the complexity in the raw material supply chain as drugmakers look to source ingredients from lower-cost areas such as Asia. The recent string of cases involving contamination, substitution and adulteration of ingredients - notably involving heparin, melamine and diethylene glycol - that have led to patient deaths provide a stark reminder of the importance of maintaining supply chain security.

Managing contractor and supplier relationships

In consequence the FDA is placing more emphasis on the qualification by the pharmaceutical manufacturer of their raw material suppliers - both for selection and monitoring throughout the lifecycle of a business relationship. The agency is now looking at this very closely, both in terms of pre-approval and ongoing surveillance inspections.

One key aspect of qualification has been to assure that drugmakers know the identity of the original manufacturer of their ingredient, and not just the distributor.

“This has become a very big problem,” said Friedman. Regulating this is immensely difficult for authorities, and while great efforts have been to step up inspection and enforcement activity in both established and developing countries, it is imperative that the pharmaceutical industry steps up to tackle the issue.

“Unfortunately authorities tend to be overwhelmed by the sheer scale of commerce taking place in the ingredient sector, and that has created something of a ‘Wild West’ scenario which can only really be curtailed by companies taking responsibility for knowing their supply chains,” according to Friedman.

For this reason, he said, the FDA is encouraging the use of track and trace technologies so that pharmaceutical companies know the identity of all the parties in the ingredient supply chain. Many firms have already started to implement this approach to track finished drug product distribution.

Meanwhile, outsourcing of manufacturing has become the norm rather than the exception in the pharmaceutical industry, and monitoring a contractor facility that is far away - or indeed close by but with a very different operating philosophy from the contracting firm - can be a challenging enterprise.

Under US law, the contracted firm is an extension of the contract giver’s operation, so the latter has full responsibility to ensure that product is manufactured in accordance with GMP. The FDA is considering making drugmakers even more accountable for problems at their manufacturing partners, for example by sending warning letters to the contract giver as well as the contractor if a deviation is discovered during an inspection.

Maintaining open and effective channels of communication with contractors is the key to avoiding non-compliance, but unfortunately there have been a number of instances in which contracted companies have been unwilling to share critical information such as process development knowledge and drug application commitments with their outsourcing partners, said Friedman.

“It is critical to transfer technology effectively from the process development stage to commercial operations to assure that the critical quality attributes of the product are delivered every day reproducibly.

“If contracting companies do not share that knowhow, the outsourcing company cannot know what impact day-to-day decisions on processes can have on the quality and performance of a product,” he noted, adding: “There have already been a few instances where a recall has been directly attributable to a lack of communication between the pharmaceutical company and contract manufacturer.”

The FDA has responded to the increasing complexity in pharmaceutical manufacturing with a number of initiatives. For raw materials, these include the development of new analytical methods for glycerin, melamine and heparin and the recently-announced PREDICT scheme, which will put in place a risk-based approach to screening shipments on entry into the USA.

Inspection and enforcement activities have been bolstered by the opening of satellite FDA offices in other countries, notably China, India, Europe and Costa Rica, while the agency is also piloting shared inspections with other regulatory authorities, such as the European Medicines Agency (EMA) and Australia’s Therapeutic Goods Administration (TGA).

International collaboration and outreach is of paramount importance, according to Friedman, and the FDA has run workshops in US, EU and China in collaboration with industry to brainstorm ways to improve supply chain security. There have also been strong indications of forthcoming legislation that has the potential to provide the agency with modern authority to better protect the borders from raw materials and drug products shipped through an uncertain supply chain.

“Updating our legislative authorities to deal with today’s problems and increased resources will provide the foundation we need to regulate in a global environment,” said Friedman.

Corporate responsibility

The responsibility of senior management lies at the heart of all these factors, as ultimately it is up to them to encourage daily adherence to GMP and, where violations occur, identify and act upon them quickly.

“FDA is really looking for evidence of effective self-governance when it inspects manufacturing sites,” says Friedman, noting that complacency for even one day means that a company can produce a defective product which “could potentially place thousands of consumers at risk of ineffective, unsafe or poor quality drugs.

“We think that the industry has done an uneven job of selecting and managing contractors,” he added. “FDA continues to underscore the importance of senior industry managers in evaluating the effectiveness of their quality agreements.”

Sponsors need to have frank and open upfront discussions with contractors, conduct a thorough initial audit, establish effective quality agreements and schedule ongoing audits to make sure that a facility remains capable, in line with the tenets laid out in the International Conference on Harmonization’s ICH Q10 document on Pharmaceutical Quality Systems and the FDA’s own guidance.

The FDA is contemplating preparing additional guidance on quality agreements to promote better choices by industry when selecting and overseeing contract manufacturers, for example by offering insight into the types of process and organisational changes that should be communicated back and forth.

It is not just the handling of contractors and suppliers that can be improved, however, and there are plenty of opportunities within companies to tighten up quality systems.

“FDA’s expectation is that the industry will move towards more modern equipment and process control - from manually-intensive processes to automation, and moving controls upstream in the process rather than relying on quality control testing of end product to evaluate batch quality,” said Friedman.

The agency would also like to see better test methods, including more statistically robust sampling plans for processes that can use Process Analytical Technology approaches to enhance control.

Better testing methods should also allow the identification of problems early on with raw material or in-process product, and putting the right quality indicators in place will help companies to monitor process performance and identify problems before product failures occur.

The emerging concepts of Quality by Design (QbD) and design space as laid out in ICH Q8 on product and process understanding, ICH Q9 on quality risk management and ICH Q10 on quality systems will help also help to improve process predictability.

“QbD provides a strong platform to launch process realisation and maintenance throughout the product lifecycle. At the centre of this process validation lifecycle is maintaining a state of control through prompt and continual improvements under robust quality systems,” he said. “It is a continuum, and learning builds starting from process design experiments carried out during development through to scale up and the commercial production when more understanding of variables is gained, especially with respect to raw materials, at commercial scale.”

Future developments

Meanwhile, the coming years are likely to see wider use of track-and-trace technologies and procedures in the raw materials supply chain, and the development of better analytics to check the identity and quality of ingredients, particularly to guard against economically-motivated adulteration such as the deliberate adulteration of heparin with oversulphated chondroitin sulphate in 2008.

From a regulatory perspective the FDA is also looking into the concept of extra-territoriality, in other words clarification of the regulatory powers of the agency to deal with overseas entities that are marketing products for the US market.

“It could be valuable for the FDA to take more robust regulatory action overseas if needed,” said Friedman. Currently the agency has a limited set of tools where conduct occurs in other jurisdictions, and it would be good to have additional tools to deal with such circumstances.

Finally, the agency is also exploring the possibility of assigning manufacturing sites with a unique identifier number, similar to the DUNS (Data Universal Numbering System) number developed by Dun & Bradstreet to identify individual operating companies, he said. Such a system could be used to prevent confusion arising between facilities.

Summing up, Friedman said: “There is a lot of attention at the moment on how FDA is approaching out-of-compliance firm and it’s a very positive development that the media is attuned to the types of failures that are occurring in the pharmaceutical industry, which often can be traced back to inattention by senior management.”

He noted that only industry management is at the site everyday and they are vested with the vital responsibility of assuring product quality of every batch produced. FDA and the other inspectorates only show up at sites periodically.

“Only through robust quality management systems can a drug company prevent unexpected manufacturing problems and product failures. More companies seem to be realising that they avoid having to go down the route of costly product failures and recalls by building robust quality systems that assure daily CGMP conformance.”

“The bottom line is that FDA is taking a very close look at companies’ quality systems, and are poised to take action if a firm lacks the right corporate governance to assure product quality, and by that we mean ‘every batch, every day, every dose’.

“Companies who fail to implement these systems could see FDA knocking on their door very soon."

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