Many sponsors outsource manufacturing their Active Pharmaceutical Ingredients (APIs) for Phases I, 2 and 3 clinical trials to CDMOs that are ideally suited for their projects. Once the Investigational New Drug (IND) is filed, those clinical trials begin with submission of safety data, which indicates there is no known toxicity going into a Phase 1 trial, confirming safety for use in humans.
As projects move deeper into clinical trials and ultimately into the clinic, additional data submission is required by the regulatory agencies. Much of that data to be submitted by the CDMO includes all aspects of the CMC (Chemistry Manufacturing and Controls).
In addition to requirements for new drug substances, there are also numerous reporting requirements for the generic drug substances we manufacture.
The need for the smooth regulatory path required to get a drug to market is the main reason pharmaceutical companies look closely at a CDMO’s track record. Preparing for and working with the FDA, EMA and other world regulatory bodies requires a copious amount of work. Glitches and delays in regulatory submissions can hinder a sponsor’s progress in bringing a new drug to market—and help its competitors.
Annual Reports
Some requirements seem reasonably simple, such as filing a required annual report within 60 days of the anniversary of an IND application going into effect. It’s hard to fathom how companies neglect to do that, but many do. As a result, the FDA rescinds many drug candidates for failure to comply, despite the fact that the regulations are straightforward and clearly spelled out.
As a regulatory-minded CDMO, Seqens North America builds regulatory requirements into every single project, from the first day forward. The steady stream of reports we file, including annual reports, pertain to the commercial actives we manufacture as well as generics. Sponsors know we can be relied on not to miss deadlines and to provide all the information needed by the agencies.
There’s more to meeting regulatory requirements than reports
For actives we produce commercially, we not only have to file an annual update, but we also have to put a batch on stability for every product that is approved in the United States. Rules change over time.
The information we collect and report on with regard to stability studies also includes details such as:
- Storage conditions
- Strength
- API batch numbers
- Batch size
- Container closure system including orientation (e.g. erect, inverted, on-side) where applicable
- Completed (and proposed) test intervals.
Staying current on regulations
Which brings us to another major CDMO time commitment: staying current on the many regulations and changes. The ICH, the FDA, and EMA all have subsidiaries that update or change pertinent regulations as the science advances. Not only do we have to stay on top of those, but we also have to monitor the Code of Federal Regulations (CFR), which publishes frequently, for any relevant updates.
Staying current and filing timely reports is in itself a big job, particularly since the details of creating new chemistry for each project add so much complexity to an already complicated undertaking. Experienced CDMOs know what the regulators need, stay atop new regulations, and deliver pristine reports that keep projects moving to their conclusion.
Regulating generic drugs – GDUFA disappoints
There is a great need and political will to lower the cost of drugs. Generics are one way to do that. To be approved by the FDA, all generic drugs have to be of the same high quality, strength, purity, and stability as brand-name drugs. As the developer of the active ingredients for several generic drugs, we provide that data to the agency.
We are also subject to FDA facility inspections to make certain the generic manufacturing and testing we do comply with all aspects of GMP.
Several years ago, the FDA implemented the generic drug users fee act (GDUFA), requiring all CDMOs to pay fees to the agency, which generates $300-$500 million annually. One of GDUFA’s goals was to expedite reviews, which the agency claims to have done. However, to level the playing field and assure high quality raw materials and intermediaries, the FDA also agreed to significantly increase oversight of substandard overseas facilities, many of them undercutting Western suppliers.
But GDUFA, renewed last year, has yet to fulfil that mandate. Still, the fees must be paid. Otherwise the products are considered adulterated and hence disqualified from sale in the U.S. The FDA has disappointed by not overseeing as many overseas facilities that produce substandard products as expected. Fortunately, sponsors are waking up to the fact that sourcing these cheaper products from substandard providers only lengthens the regulatory process and adds significant costs.
For other articles on this topic, check out: “Practical Tips for Working With Your CMO When Preparing for Phase 1 Clinical Trials Invest in your NCE asset to assure quality and avoid regulatory delays” and “Despite all the Rhetoric, Time-Consuming FDA Guidelines Make More Work for CMOs but Safe Products for Consumers.” And please call us at (978) 462-5555 to discuss this topic further.
Summary
The cost of developing and manufacturing new drug substances seems high – until one realizes just how much effort and skilled personnel the job entails. Keeping up with and adhering to regulatory requirements is just one aspect. But done methodically by a regulatory-minded CDMO, whether for commercial products or generic drug substances, it saves sponsors both time and money.