FDA Ushers In Era of New Drug Manufacturing Technologies

One new drug after another, manufactured the same way as ever, that's how the pharmaceutical industry has always operated. But times are changing, and a small team of reviewers at FDA is guiding an array of new manufacturing technologies through the agency's regulatory review process.

Certainly, heads nodded with recognition at a recent conference session on emerging technologies as an attendee complained that aseptic processing technologies haven’t changed in the 35 years since he started out as a sterile filling operator.

But today, manufacturing innovations are creating niche markets, lending new life to old brands and potentially transforming the structure of the industry. And they're even bringing change to aseptic processing.

More Than Just Continuous

The Emerging Technology Team in FDA's Center for Drug Evaluation and Research is best known for its work helping the industry transition from batch to continuous manufacturing methodologies.

After the team formed in 2013, it focused initially on reviewing applications to market drugs that would be manufactured continuously.

One of those applications, for Vertex Pharmaceuticals Inc.'s new cystic fibrosis treatment, Orkambi (lumacaftor/ivacaftor), won FDA approval last July.

In another case, the team coordinated FDA's review of Janssen Products LP's supplemental new drug application to switch its HIV-1 treatment Prezista (darunavir) from batch to continuous manufacturing, which the agency approved this April.

The team has become synonymous in the minds of many with continuous manufacturing as Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, and other agency officials press industry to consider the advantages of going continuous.

The pressure has only increased with the publication last month of a report from the White House's National Science and Technology Council that counts continuous manufacturing of pharmaceuticals as one of the priority technology areas that the government, industry and academia should promote in the interests of US competitiveness.

Even though December 2015 draft guidance on how companies can work with the team to advance their emerging technology applications doesn't mention continuous manufacturing, industry comments on the draft focus squarely on it.

The Generic Pharmaceutical Association said generics firms worry about business challenges that come with continuous manufacturing, while the Pharmaceutical and Research Manufacturers of America anticipates business advantages from it.

But while the pharmaceutical industry's generics and brand sectors debate the merits of continuous manufacturing, individual companies are pursuing other emerging technologies with the team's help.

Continuous manufacturing animation

This animation illustrates one vendor's approach to continuous manufacturing of tablets.

Source: Gericke and Gerteis

FDA Swallows 3D Printing Idea

Lawrence Yu told a Parenteral Drug Association workshop last September that he knew well the difficulty of getting the agency to approve new technologies.

"I have experience at FDA for more than 16 years," the deputy director of the Office of Pharmaceutical Quality in the agency's center for drugs said. "When new things happened, a lot of debate and discussion happened."

But when something new came along recently – a proposal from a niche firm, Aprecia Pharmaceuticals Co., to manufacture tablets with a 3D printer instead of a tablet press so they wouldn't be so hard to swallow – the agency was ready. The Emerging Technology Team and other regulatory innovations enabled it to approve that application July 31 within the timeline specified under the 1992 Prescription Drug User Fee Act, or PDUFA.

The agency used its new team-based approach to review the proposal, and assigned a member of the Emerging Technology Team to lead the application review team.

FDA also applied a new risk-based approach to the review to keep it focused on the most important issues.

Importantly, the team members participated in the pre-approval inspection.

"With so many new things going on with this specific application," Yu said that "without evolving thinking, without our Emerging Technology Team, without integration of the inspection, without the team-based integrated quality assessment, it's hard to imagine for me that this application could be approved on time."

One concern Yu said the team raised during the review was that the dosage form might not be strong enough. But in the end, the team agreed it was strong enough to be shipped.

Sanjay Sehgal, Aprecia's VP for regulatory affairs and conformance, also discussed the issue of Spritam's tablet strength in his Jan. 26 remarks at the International Forum and Exhibition on Process Analytical Technology (Process Analysis & Control), known as the IFPAC conference, in Arlington, Va.

Aprecia makes the tablets, which orally disperse with a sip of water in just five to 15 seconds, by alternately spreading thin layers of powder blend and depositing pre-programmed patterns of liquid droplets that contain active ingredient and bind the powder.

Sehgal said Aprecia carefully monitors hardness and dries the tablets under proprietary conditions to make sure they can be handled and transported.

Tablet printing animation

This animation illustrates how Aprecia prints tablets.

Source: Aprecia Pharmaceuticals

But Agency Chokes On Digital Med

Another emerging-technology application didn't fare as well.

This one would give new life to Otsuka Pharmaceutical Co. Ltd.'s aging Abilify (aripiprazole), an atypical antipsychotic FDA had approved in November 2002 for treatment of schizophrenia.

A few months after FDA last year approved four generic versions of aripiprazole, the agency received a new drug application from Tokyo-based Otsuka and Proteus Digital Health Inc., of Redwood City, Calif., to add sensors to medicines that show whether they're actually being taken.

They proposed a new product, an Abilify tablet with an ingestible sensor from Proteus in it so that family, caregivers and patients themselves could determine whether they've been taking all their doses.

When the sensor reaches the stomach, it signals a wearable patch, which records and time stamps the information and collects other information such as rest, body angle and activity patterns, and relays it to the patient's mobile phones or other Bluetooth-enabled devices and, if the patient has consented, to physicians and caregivers, Proteus says.

Otsuka said FDA on April 27 issued a complete response letter for the combination product, asking for more information about how it might perform in the real world. The agency specifically requested further human factors investigations "to evaluate use-related risks and confirm that users can use the device safely and effectively," Otsuka said in a press release that day.

Taking 'Baby Steps' Advised

One member of FDA's Emerging Technology Team, Geoffrey Wu, recently shared his thoughts on potential approaches companies can use to reduce risk when adopting new technologies like continuous manufacturing.

One option is to take a "transformation approach," in which instead of going straight from batch to continuous, you first adopt a hybrid approach, Wu, who is with FDA's Office of Lifecycle Drug Products, told a Jan. 27 generic drugs session at the IFPAC conference.

"The beauty of this is because you can still keep the downstream as batch steps, so there will be less risk of affecting the final drug product properties," Wu said, adding that later, when you're ready, you can advance to "full-blown" continuous manufacturing.

Another option is what Wu calls a "lifecycle approach." This involves applying an emerging technology on a test bed so you can learn how to use it without disrupting commercial production. Once you've worked out the kinks, you send a supplement to the agency and prepare to shift production over to the new technology.

A related option is a "parallel approach," which involves keeping both systems running in parallel to further reduce technology risk.

Finally, Wu described what he calls a "complexity approach," which involves starting with the simplest component of a complex new technology like continuous manufacturing and working toward the most complex.

For continuous manufacturing, for example, he said, "I would take the direct compression process to begin with and play with all the PAT (process analytical technology) tools, monitoring the tablet, the product, and once I'm proficient with that I would move on to a dry granulation process, which is a little bit more complex but still less complex than a wet granulation process. Just one example so that you can take baby steps if you have the luxury and such a big portfolio that you can play around with different technologies or during operations, for instance."

Why New Technologies For Generics

Although generics firms have remained content to let brand firms take the lead on technology, including manufacturing technology, Wu made a pitch for them to pursue emerging technologies.

Pharmaceutical quality means safety, efficacy, affordability and availability, which is what generics are all about, he said. A generic drug molecule can be "rock solid," he said, "but if the manufacturing process is screwed up, the design is screwed up, then no safety can be assured, no efficacy, and don't even worry about availability and affordability."

He encouraged companies to make sure the emerging technologies they develop are fit for purpose, avoiding, for example, process analytical technology probes that are too complex for the processes they're supposed to measure.

And he encouraged companies that are looking to use new technologies to start talking with FDA's Emerging Technology Team early. That way, he said, "we can understand the technology better so we can do a better job in our regulatory review process."

New Technologies Yield New Strategies

In the glory days of serial blockbuster drug launches, manufacturing technology was just an afterthought, but that has changed. Today, new manufacturing technologies play a growing role in business strategy.

Company officials have highlighted the way their investments in continuous manufacturing relate to their business strategies, and for each company, it's different (Also see "Continuous Manufacturing Poised to Disrupt Pharma Sector" - Pink Sheet, 29 Jul, 2014.):

• Eli Lilly & Co. is using it to increase the range of chemistry possibilities.
• Vertex Pharmaceuticals Inc. is using it to increase speed to market.
• Others are intent on using it to reunite the manufacture of drug substances and products.
• Still others view it as a way to penetrate emerging markets by decentralizing their manufacturing operations.

Proteus' Strategy

Proteus, developer of the sensor that Otsuka wants to put in Abilify tablets to show when and whether they were swallowed, is moving ahead with plans to use the sensor with other drug products that also are in therapeutic areas where medication adherence can be an issue.

In January, the company announced an arrangement with Barton Health, a health system in Lake Tahoe, Calif., to help patients with uncontrolled and co-morbid hypertension and their physicians make sure they take their blood pressure medications and get the daily exercise they need.

Rather than rely on manufacturers to press the FDA-approved sensors into their tablets, Proteus and Barton Health are relying on a specialty pharmacy to co-encapsulate the sensors with each patient's medications.

The sensors report via wearable patches and Bluetooth devices not only the time of ingestion but also heart rate, activity and rest data.

Proteus presented interim results at a cardiology meeting in April of a clinical study that indicated the sensor-enabled medicines, the wearable patch and applications for patients and care givers reduced blood pressure and bad cholesterol in patients with uncontrolled hypertension and type 2 diabetes.

Aprecia's Strategy

Aprecia, the company that won approval for a 3D-printed tablet, has a business model that's also built around a technology solution to poor adherence: The technology makes it easy to take drugs that patients otherwise might forgo because they're difficult to swallow.

The company, formed in 2003, obtained an exclusive license from the Massachusetts Technology Institute for the application of a 3D printing technology it developed to pharmaceuticals. In 2007, Aprecia developed its ZipDose platform for fast-melting orodispersible tablets.

Its first product, Spritam, is a 3D-printed formulation of the antiepileptic drug levetiracetam. The brand version, UCB Inc.'s Keppra, was approved in 1999 for 250, 500 and 750 mg dosages. Generic approvals began in November 2008, and numerous generic versions have since been approved.

"Swallowing difficulties can affect drug adherence and result in increased comorbidities or mortality," Aprecia's Sanjay Sehgal told the IFPAC conference.

Tablets and capsules can be hard to swallow, especially in the 500-plus milligram range, and with older patients, as dysphagia increases with age, he said. Liquid formulations can work, although for epilepsy, lack of precise dosing can be an issue, he said.

Other fast-melt technologies on the market – soft-compressed tablets, film strips and freeze dried products – can only enable dosing of 30 mg, 25 mg and 250 mg respectively, he said, whereas Aprecia's ZipDose technology enables 1,000 mg dosing.

Aprecia has several other products in development that could provide alternatives to highly prescribed but hard-to-swallow high dose drug products.

Other 3D Printing Niches

There are other potential niches for 3D tablet printing technology, Akm Khairuzzaman of FDA's Office of Pharmaceutical Quality told the IFPAC conference.

It could enable more advanced, potentially more effective drug release profiles.

It could enable personalized dosing, perhaps with a drop-on-demand inket dispensing custom doses onto print film, which could help with highly potent drugs, growing children, multi-drug polypills, patient-specific implants and custom tablet shapes.

It also could enable on-demand manufacturing of drugs with limited shelf lives, providing expanded capability for emergency medicines and breakthrough products.

Khairuzzaman rated 3D printing high for complex products, personalization and manufacturing on demand, but low for throughput, tolerance and mechanical integrity. And he acknowledged some of its process considerations and limitations.

He noted as well that existing regulatory pathways don't align well with personalization due to their requirements for consistent quality.

Other Technologies Under Review

Wu noted that FDA's Emerging Technology Team has been reviewing a diverse array of technologies.

For example, he said, "we have encountered some new container closure systems using … superior material construction to avoid for instance glass delamination [and] particle generation in sterile products."

And there are even a couple of innovations in aseptic processing.

Wu said one innovation involves "a new sterile filling technology that can potentially be found in non-controlled environments."

The other is "a completely enclosed robotic arm that can be used for sterile compounding." It can be used "to completely exclude human interaction from the compounding process using computer-controlled robotic design," Wu said.

"I'm so amazed," he concluded, "to see all these technologies going through the agency, we have evaluated, provided our feedback and these folks are moving along."