Parenteral control - challenges of formulating novel excipients

7 April 2017



While continuing to occupy a smaller market share of drug delivery than oral solid dosage, parenteral formulations are today a major focal point – not least because of rapidly growing interest in biopharmaceuticals. Meanwhile, parenteral-grade excipients continue to be in short supply, are expensive to produce and require stringent test data. Sarah Williams speaks to Sandeep Nema, executive director portfolio and project management, global biologics, at Pfizer, about the challenges of formulating novel excipients, how the industry has progressed in recent years and where future developments might lead.


A fast track to the bloodstream, nervous system or specified part of the body, parenteral formulations allow a swift and targeted delivery of drugs. But since this also means bypassing the body’s natural filters and defence mechanisms, the quality, purity and isotonic values of such medication are critical. Excipients are central to a successful delivery, but can also be problematic when it comes to a safe, stable formulation, and requirements for cGMP are extremely high. While there is much crossover between excipients used within oral solid dosage forms and parenteral formulations, few manufacturers are prepared to commit to the investment, stringent testing, and enhanced risk factors involved in producing these chemicals to parenteral grade.

Sandeep Nema, executive director portfolio and project management, global biologics, at Pfizer, has long tracked progress in the field. Co-editor of the three-part series Pharmaceutical Dosage Forms: Parenteral Medications (currently on its third edition), he has also served as a steering committee member for the Handbook of Pharmaceutical Excipients.

But as the lead formulator of four commercially launched drug products, he has also contributed directly to developments himself. Responsible in his current position for all pre-proof-of-concept biologics projects from discovery up to the beginning of phase III at Pfizer in St Louis, he previously established a protein pharmaceutical R&D group that included microbiology and stability functions.

Safety first

“Because of the route of administration for the parenteral dosage form, there are only very limited sets of excipients that have been approved,” Nema says.

“To achieve a new excipient approval, you have to ensure there is enough safety data available, and that the toxicity studies have been done. So, if you want to go to anything novel, a whole new set of challenges and additional time and cost need to be covered.

“Many formulators therefore tend to use the excipients that already have a precedent in another injectable dosage form. In other words, the choice is limited.”

Too small to be captured by the regular filtering methods used by excipient manufacturers to remove bacteria, endotoxins must instead be eliminated through more complex – and expensive – processes. Consequently, parenteral grade excipients can cost as much as five times more to produce than those for oral formulations.

Needs must

The strict purity requirements for parenteral excipients are reflected in regulation concerning cGMP, however drug formulators also need to consider potentially higher needs dependent on the specific product being created.

“There may be one or two parenteral grades that we will specify,” says Nema, “but then we look at the specific product requirements, based on what we know about the biological drug molecule, and then we impose extra testing and extra specifications that a lot of times aren’t required by the pharmacopoeia for some of the ingredients.

“For example, you may know that a particular protein in the parenteral dosage form is susceptible to specific heavy metals, so then we would do extra testing around that.”

There are now a lot of new modalities coming in, whether its gene therapy or cell therapy – and these will also drive the development of novel excipients because they will require functions that those currently available are likely unable to provide.

Though it is commonly large molecules that tend towards instability, with small molecule drugs more stable, there are always exceptions, Nema cautions. A comprehensive understanding of the product in hand is therefore vital to achieving a safe, effective parenteral drug.

While traditional stability analysis is still important, Nema sees high-throughput techniques used at the initial screening stage as providing a swift and helpful method for evaluating the impact of many different excipients on the stability of the molecule.

“Formulation scientists are using high-throughput methods like differential scanning calorimetry, biophysical methods, circular dichroism, dynamic light scattering, fluorescence spectroscopy, to screen and gain knowledge of which potential excipients will be useful in maintaining stability/activity, and which should not be used,” he says.

At the same time, Nema would like to see the focus extend beyond chemical and physical analysis to include the actual functionality of the excipient itself. While not intended to have an active effect on patients, many excipients are not in fact inert – and the effect of combining several within a formulation is an important consideration.

Make the grade

Parenteral-grade excipients that FDA may have approved in a drug product can present issues such as potentiation or inactivation when combined with other drugs or excipients present in the formulation.

Formulators must also consider the route or administration – whether intravenous, subcutaneous or intraspinal – as well as the concentration of the active ingredient and the details of the delivery method itself.

“If you have to inject intraspinally, for some of the central nervous system drugs or anaesthetics like an epidural, then there are even more stringent requirements regarding endotoxins,” Nema says. “Now, since for a lot of this the excipients are a major part of the formulation, then you may have to then have specification criteria defined by that route of administration.”

Whether a drug is administered via a single-use or multi-use receptacle naturally has an impact on the antimicrobial requirements of that drug. Excipients can provide this protection, but there are also limits on the content permitted in a parenteral drug.

“A lot of regulatory agencies would prefer a single-use device that doesn’t require preservatives, as some preservative excipients can cause adverse events, or may themselves be toxic,” Nema says. “But, on the other hand, from a patient perspective, there are occasions where they really want a preservative solution.

“Take an insulin pen: patients want something that they can use for ten days or a month, and in that case you need to make sure that as the formulator you are adding exactly the right amount of excipient to balance the required antimicrobial effect against any risk of an adverse event.”

Take stock

While Nema has followed developments within parenteral excipients with interest, twice reviewing the current state of play for the PDA Journal of Pharmaceutical Science and Technology (first in 1997 and again in 2011), he feels that progress has been slow and significant ‘breakthroughs’ have as yet been unforthcoming.

Taking into account Nema’s current role within biologics projects, however, his optimism concerning the direction of future developments is unsurprising and heartening.

“There are now a lot of new modalities coming in, whether its gene therapy or cell therapy – and these will also drive the development of novel excipients because they will require functions that those currently available are likely unable to provide,” he says.

Here again, preservative excipients could be key, with the functional properties of live cells needing to be safeguarded before delivery – without then introducing toxic substances into patients during injection. Formulators will also look to excipients to provide more efficient clinically relevant methods of preservation; in stem cell, CART or gene therapy products that use viral vector, for example, where cells currently need to be carefully frozen to -80 or -132°C and thawed to room temperature before administration to patients.

Slower, larger

Excipients could also play a role in establishing the sought-after goal of slow-release formulations for large-molecule parenteral drugs. It may be an area that has caused excitement in recent years, but endeavours in the industry so far have been hit and miss, and much more work is needed, Nema argues.

“It’s more difficult than with small molecules, because obviously in many cases you cannot use organic solvents, or heat the solution because that can denature the protein,” he says. “For now, very limited sustained-release nanoparticles or microparticles formulations have made it into commercial products, so there is a lot of opportunity to work in this area, to look at the potential of new excipients to help the formulator.

If a platform technology can be created – a polymer that can be applied to a variety of protein molecules for use in parenteral – that could be very useful.

“If a platform technology can be created – a polymer that can be applied to a variety of protein molecules for use in parenteral – that could be very useful.”

Regulatory changes are also afoot. From 5 May 2017, all-new drug master files (DMFs) must be submitted electronically to FDA, including the Type IV DMF, which concerns excipients.

This, Nema feels, could place further pressure on excipient manufacturers, and the benefits of the new system will depend on their willingness to embrace the new requirements.

“In the long run, it could be a good thing all round, but it’s a matter of how prepared excipient manufacturers are to submit [information to FDA] themselves,” he says.

“The other option would be that all of that needs to be filed by the innovator. This relies on how much information the excipient manufacturer has provided and how simple is it for the innovator to review it. Because if you are making a drug, all of that information needs to come into the original DMF application, so either approach could be complicated.”

Working together

Cloud solutions could prove helpful, but so will continued efforts to harmonise the regulatory framework between markets and regions. And with direct supply agreements between manufacturer and innovator in many cases helping to shore up the supply of these costly, parenteral-grade excipients, greater collaboration on regulatory applications could also pave the way to more safe parenteral grades entering the market.

Producing excipients to parenteral grade is a big commitment.
The method of administration has a direct bearing on the kind on the regulatory criteria excipients must satisfy.


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