New drug compounds, particularly those for intended use in oncology, are becoming increasingly more selective in their interaction with biological targets, with pharmacological activity often being achieved with minute amounts of drug. The manufacture of highly potent drug substances and their drug products requires particular care and attention in ensuring the safety for those involved in the handling of the materials. Also, as products containing highly potent drugs often contain very small quantities of the drug per unit dose, it is essential that during the processing stage, satisfactory uniformity of dose across an entire batch is achieved.

For safe handling of highly potent — and often highly toxic — materials, manufacturing practices have moved away from reliance on personal protective equipment (PPE) alone (e.g. air-line suits), with current practices focusing on “containment at source,” using isolator technologies, to prevent operator exposure to such compounds during processing¹. So given a new drug entity, how do we categorize it based on its potency — and hence decide what measures are required in handling it?

In recent years, a number of systems have been proposed for categorizing drug substances according to their potency, based on the use of occupational exposure limits (OELs) or occupational exposure bands (OEBs). Probably the most widely used system is that devised by the industrial hygiene consultancy, SafeBridge, which is a four-category system (category 1 = low toxicity; category 4 = high potency)². An example of a typical potency classification system is shown in Figure 1.


As a general rule-of-thumb, a ‘potent’ drug can be defined as:

• Having biological activity at ≤150 µg per kg body mass in humans (equivalent to a therapeutic dose ≤ 10 mg), or . . .
• Having an OEL ≤ 10 µg/m3 air, as an eight-hour time –weighted average, or . . .
• Having high pharmacological selectivity and/or with potential to cause cancer, cell mutations, reproductive toxicology at low doses, or . . .
• A new compound with unknown or incomplete potency/toxicological assessment.

Typically, a compound can be considered ‘highly potent’ if the therapeutic dose is less than 1 mg. A few examples of commercial products that fall into the highly potent category are digoxin (Linoxin capsules, 100 µg per capsule) and alprazolam (Xanax tablets, 250 µg per tablet). A particularly highly potent compound with respect to its pharmacological activity is calcitriol (Rocaltrol, 0.25 µg per capsule).

The safe handling of potent drug substances is not the only challenge associated with development and manufacturing activities. Consideration also has to be given to the practicalities of producing a homogeneous batch of product with unit doses containing very small quantities of drug. Also, there may well be challenges in the determination of drug content in unit doses — and certainly there can be problems in detection limits for swab samples taken for equipment cleaning verification.

So, given the task of producing an oral dosage form for a new oncology drug at a dose of 10 µg per unit dose, what is the best formulation strategy?

A good starting point is to consider incorporating the drug in a liquid vehicle and to encapsulate the formulation in a hard shell or soft gel capsule³. In general, it should be possible to dissolve the very low concentrations of drug in an appropriate vehicle suitable for encapsulation.
The benefits of the liquid encapsulation approach are:

• Significant reduction of risk of exposure to operator if the drug is dissolved/dispersed in a liquid vehicle (i.e. no airbourne dust is generated, as is common during the process stages of tablet manufacture). The operator is at highest risk during dispensing of the drug and addition of the drug to an aliquot of the vehicle — and these steps can easily be conducted in a containment hood or isolator.
• Dissolution of the drug in a liquid offers the best opportunity to achieve satisfactory uniformity of dose for low-dose products. For example, a dose of 10 µg of the drug in a capsule containing 200 mg of formulation would equate to attempting to equally distribute 250 mg of drug in 5 kg of powder blend. This is not an easy task if a conventional powder or granule approach was considered, even with micronized drug. It is a much easier task to dissolve 250 mg in a portion of the solvent, mix the pre-blend into the remainder of the solvent and then fill this solution into capsules. Filling of liquids into capsules can be achieved with a high degree of accuracy and control over fill weight. Also, the technology is now established for filling liquids into conventional hard-shell capsules (gelatin or HPMC) rather than having to rely on filling into soft-gel capsules, which requires specialized equipment and expertise.
• Alternatively, if a liquid-in-capsule presentation is not possible, then a granule formulation can be considered (for encapsulation or compression into tablets). The way to ensure satisfactory distribution of the drug throughout a powder or granule batch is to adopt a wet-granulation process approach and to pre-dissolve the drug in the granulation fluid (e.g. water or isopropyl alcohol, depending on solubility characteristics of the drug substance) and to spray this solution onto the powder bed or granule mass while mixing the powder in a high shear mixer. The solvent can then be removed by conventional tray drying or fluid bed drying. This approach has been successfully used to produce tablets containing as little as 2.5 µg of drug, with a relative standard deviation (RSD) of < 2%.

For either of the approaches described above, processing can be optimized by using a ‘surrogate’ compound as a substitute for the drug substance. The surrogate needs to exhibit similar solubility behaviour to the drug substance and must be easily detectable at low levels (e.g. have a high molar extinction co-efficient, for UV detection). Most important, the surrogate needs to be a low potency/toxicity compound (preferably an excipient). A good surrogate for water-soluble potent compounds is sodium benzoate, which can be detected at very low levels using high-performance liquid chromatography (HPLC) with UV detection. A good surrogate for poorly water-soluble potent compounds is fluorescein.

Analysis of High Potency/Low Dose Products
An additional challenge in developing high potency, low dose drug products is the analysis of drug-related samples. As you would expect, level of detection can be an issue when determining low levels of drug in samples. If the drug molecule contains a strongly absorbing chromophore, then analysis of unit doses for drug content and degradation products should be achievable using standard HPLC UV detectors. However, for determination of drug residues for cleaning verification purposes, it is often necessary to have the capability of detecting trace amounts of drug, down to nanogram or even picogram levels. For large manufacturing equipment items, such as drums and granulators, it might be possible to swab a larger surface area to potentially capture a higher quantity of residue for analysis. However, this approach is obviously impractical for smaller items, such as tablet punches.

Acceptance criteria for drug residues on manufacturing equipment following cleaning are based typically on a fraction of the lowest dose (e.g. 1/1000th of the lowest therapeutic dose) for a particular swabbing surface area. For example, cleaning verification acceptance criteria for a product containing a dose of 50 µg drug/capsule might require that the manufacturing or packaging equipment be cleaned to a level below, say, 50 ng/100 cm2. A swab sample for this area may then be immersed in 10 mL of solvent for analysis, which would equate to the detection level needing to be down to 5 ng/mL. Even if the molecule has high molar absorptivity, detection down to this level is likely to be impractical using a traditional UV detector.

Fluorescence or electrochemical detection may be an option for specific molecules but many drug compounds would not be suitable. Mass spectrometry, however, is almost universally applicable to all small molecules and has the sensitivity to be able to detect minute traces of drug residue. Therefore, for very low level detection, liquid chromatography-mass spectrometry (LC-MS) is the most appropriate analytical method for cleaning verification purposes. LC-MS systems are also much smaller and cheaper to purchase and maintain than they were 10 to 15 years ago.

In summary, the product development and manufacture of highly potent drug substances and their products bring a number of challenges, but not insurmountable obstacles. Technologies to ensure safe handling procedures have now become widely available (e.g. isolators, split butterfly valves). Formulation strategies for ensuring homogeneity of low dose products are well established and although challenging, the detection of very low levels of drug substances is achievable — using the appropriate techniques. 

References

1. Bormett, D. High-Potency APIs: Containment and Handling Issues.  Pharm. Technol. (Sept. 2008)
2. Farris, J.P., Ader, A.W. and Ku, R.H.  History, implementation and evolution of the pharmaceutical hazard categorization and control system.  Chem. Today (Apr. 2006), 24: 5-10
3. Carey, J and Dixon, A.  Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs.  Pharm. Technol. (Apr. 2008)

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Robert Harris is chief technical officer at Molecular Profiles, a provider of pharmaceutical development services including formulation & analytical development and clinical trial manufacturing up through Phase II. For more information, please contact molecular@scottpr.com.