A topical drug is typically a semi-solid formulation and may be a gel, cream, lotion, or ointment. Other topical dosage forms (e.g., powders, sprays, and solutions) are beyond the scope of this discussion. A quality-by-design (QbD) approach can be used to develop an understanding of the process and identify process parameters that will affect the quality of the product. Pharmaceutical Technology spoke with Jeffrey S. Reynolds, associate director, Pharmaceutical Sciences, at Tergus Pharma, a pharmaceutical research, development, testing, and clinical manufacturing company specializing in topical drug formulation and in using QbD for drug product design, about what to consider when developing a manufacturing process for topical drugs.
Early process development
PharmTech: What are the key considerations for manufacturing of a topical drug?
Reynolds (Tergus): A suitable process can be tricky to develop for a semi-solid product, particularly in the early stages of development when the product and process may not be understood fully. The first aspect of deciding how to proceed with manufacturing is the type of semi-solid dosage. A cream or lotion will require a different approach for manufacturing than a gel or ointment. The type of mixing, the need for side vessels, heating, and cooling are all aspects essential to identifying the appropriate starting point for process development and subsequent technology transfer for scale up.
In general, one must consider a number of process parameters and material attributes to determine criticality and associated acceptable ranges for those critical parameters. Some parameters of interest are process temperature, heat/cooling rates, order of addition, mixing type, mixing speeds, mixing times, level of batch in tank, vacuum usage, inert atmosphere, and so on. There is no one set of parameters that will be important for every type of batch. For each product and process, its design space requires a comprehensive understanding of the critical process parameters (CPPs) and critical material attributes (CMAs) as they pertain to critical quality attributes (CQAs) of the drug product. Only then can the quality of the technology transfer and end product be guaranteed with a reasonable degree of confidence.
PharmTech: When designing a manufacturing process for a topical drug, what are some examples of CQAs and CPPs?
Reynolds (Tergus): The pre-development phase of drug product development will establish the quality target product profile (QTPP). The QTPP defines the desired end-product characteristics. These characteristics may include disease state to be addressed, dosage form, appearance, aesthetic qualities, color, viscosity, container/closure, drug concentration, dispensing configurations, pH, and microbial considerations. The preceding list is not intended as a complete or comprehensive listing of all attributes, but represents many of the quality attributes that the drug product developer would consider as part of the QTPP. Not all of these characteristics ultimately will be critical. However, the QTPP starts the process and helps to ensure a development program aligned with the desired end-product. Many, but not all, of the attributes identified in the QTPP will become CQAs. The criticality of a particular quality attribute will arise during the development phase as the understanding of the product and process becomes more comprehensive and complete.
Often, the initial QTPP will evolve and the final QTPP may not be exactly the same as the original one. It is a work in progress and intended to be dynamic document that facilitates interaction between R&D and marketing/sales. As the product development moves into understanding the process, the QTPP becomes the guiding light in identifying which process parameters are critical. Some of the typical process parameters to consider are mixing type, mixing speed, mixing time, temperature ramps, need for nitrogen or argon blanketing, UV light protection, and so on. Again, this list is not comprehensive, but it represents many of the key process parameters that may be critical to the final drug product quality.
Raw material variability
PharmTech: What challenges does raw material variability present, and how can these challenges be addressed?
Reynolds (Tergus): Raw materials or excipients in a semi-solid drug product can be some of the more challenging parameters to evaluate. On the surface, it would appear that a given material that meets the United States Pharmacopeia (USP) or European Pharmacopoeia (Ph Eur) monographs should be adequate to provide an equivalent effect in the drug product, but this is not necessarily true. In many cases, one USP/Ph Eur excipient is as good as another. Depending on the excipient, however, the specific supplier of a material may be a critical attribute. Additionally, potential CMAs can include where a specific test performed on the excipient falls within the acceptable range. In other words, for a material that routinely has been used at the upper end of a specific test range, it may not be suitable to use a lot of material that comes in at the lower end of the specification range.
Furthermore, the USP/Ph Eur monographs do not contain every critically relevant test for the material and how the material will behave in the drug product. Oftentimes, the design space analyses during development will reveal additional CMAs beyond the specific compendial requirements. For example, as many semi-solid excipients are derived from fatty alcohols and fatty acids, the chain length distribution may influence the performance of material in the drug product, even to the extent of resulting in an unacceptable product if the chain length shifts to either the shorter or longer distribution. A clear example was the pastillation of polyoxyl-2 stearyl ether. The original form (block hot pour) gave acceptable product, but the direct substitution of the pastillated form resulted in poor emulsion stability. Both met the requirements of the USP, but only the original block form was acceptable in the cream product.
PharmTech: What are some of the considerations for stability during storage and for stability testing?
Reynolds (Tergus): Drug product stability is guided by International Council for Harmonization requirements. Typically, samples are stored at a variety of conditions dependent upon the intended long-term storage condition of the product. In other words, if the drug product is intended for room temperature storage while on shelf, the stability study likely will have samples stored at 25 °C/60% relative humidity (RH), 30 °C/65% RH, and 40 °C/75% RH. These conditions are, respectively, the so-called real time, intermediate, and accelerated conditions for most stabilities. Other conditions relevant for alternative storage (refrigerated, frozen) will have a different set of conditions representing the real time, intermediate, and accelerated storage.
The intervals chosen for testing typically include 1, 3, 6, 9, 12, 24, and 36 months. Additional intervals often are included in the design to provide enhanced statistical and regression evaluation to assist in setting the initial expiry term of the drug product. Furthermore, some studies, particularly early in the development phase, may proceed only to the three-month interval.
Once the stability schedule is defined, selection of the testing requirements follows. At a minimum, the CQAs should be considered as part of the stability testing requirements. Early development programs may evaluate only the active pharmaceutical ingredient in the drug product for the purposes of screening out unacceptable dosage prototypes.
Once a product moves to the preclinical/clinical stage, the stability program will include all tests that are stability indicating, that is tests that directly reflect those characteristics that will limit the expiry term of the product. Typically, these include the active ingredient, related substances, viscosity, pH, within container content uniformity, and any ancillary stability indicating tests.
PharmTech: What are some key considerations in scaling up to commercial manufacturing?
Reynolds (Tergus): The scale up and technology transfer of a semi-solid drug product can be fraught with pitfalls and challenges. There is no one size fits all (or even most). Many of the challenges in scale-up arise from an inadequately understood product or process, more specifically the CMAs and CPPs. A semi-solid drug product that has well defined CMAs and CPPs typically has less challenges on scale-up. Furthermore, when encountering challenges, this knowledge of CMAs and CPPs gives the manufacturing team an enhanced chance of successfully overcoming the challenges. Problems encountered during the development phase along with the design space analyses gives a better understanding of how the materials and process behave and their effects on the product performance. This is not to say that statistical experimental design is the answer to everything. A well-defined and understood product and process design space gives the best chance of overcoming any challenges during technology transfer and scale-up. To enhance the chances of getting the right product on the first attempt, one must ensure the CMAs as identified during the development program are matched or demonstrated as equivalent. Using the same suppliers for each of the excipients is a good starting point. The next step is to use the same type of manufacturing vessels as used in the design space work, but this is not always practical. Many contract manufacturing organizations (CMO) have only one or two types of equipment capable of producing semi-solids. Selecting a CMO that has the most similar (or identical) equipment will give the best probably of success on transfer. But what does one do when the equipment used in development is not available at commercial scale? Selecting a manufacturing unit that has similar mixing styles to what was used in the development program is the next best path forward. Having an awareness of where the product will go for commercial manufacturing helps the development team to design a process suitable for the intended CMO. None of these challenges should be insurmountable provided the development scientists, formulators, and engineers have done a thorough job of characterizing the product and process.
Vol. 41, No. 8
When referring to this article, please cite it as J. Markarian, “Using QbD in Topical Drug Manufacturing,” Pharmaceutical Technology 41 (8) 2017.