Impact of Quality by Design on Topical Product Excipient Suppliers, Part I: A Drug Manufacturer's Perspective

QbD concerns of topical product development scientists

When focusing on topical product risk and criticality as related to raw materials, typical CQA items are phase separation, rheology, precipitation of dissolved active/excipient or particle changes in suspended active, microbial contamination, pH, assay/impurities, heavy metals, and residual solvents.

Phase separation. Phase separation of a topical product in a multi-use container can result in super-potent dosing for some of the treatment applications and sub-potent dosing for the remaining treatment applications. In the example QTPP for fluorouracil cream (7), this element was labeled “homogeneity and tube uniformity.” Phase separation can be most dramatic when the active is found primarily in the dispersed phase of a product that contains little of the dispersed phase (e.g., a hydrophobic drug that is almost completely dissolved in the oil phase of an oil-in-water emulsion that has more than 85% water). If this product is a cream that separates into a half milliliter of oil-rich phase that is at the orifice of the tube, then 90% of the drug may be applied in the first few applications. Alternatively, if the separated oil-rich phase of a lotion creams to the top of a bottle fitted with a pump that has a long dip tube, then 90% of the drug may remain inside the bottle and never be applied. Another example is when a gel containing uniformly dispersed solid-drug particles loses viscosity on storage and the previously dispersed drug falls to the bottom of the container. For topical products that are semisolids or fluid dispersions, assuring content uniformity (i.e., avoiding phase separation) tends to dominate the control strategy.

Rheology. Rheology is the science that characterizes the flow of materials. For topical products, rheology considers the impact of shear on the apparent viscosity of a non-Newtonian liquid. Rheological behavior is directly correlated to microstructure of a topical product formulation. For two products that have the same composition (qualitatively [Q1] and quantitatively [Q2] the same), if they have the same microstructure (Q3), then these two products will have the same bioavailability. The manufacturing process can have a significant impact on the formulation microstructure (6). This means that characterizing rheological behavior as a function of excipient variability, processing parameters, and even active purity or particle size distribution may provide valuable insight with regards to the microstructure of the product. Dramatic change in rheological properties may affect the bioavailability. This impact applies to rheological changes over the shelf-life of the product, lot-to-lot changes in the rheology of the product, and differences in rheological properties between a generic formulation and the reference listed drug.

Precipitation. If the API is completely dissolved in the topical product, then it must remain completely dissolved over the shelf life of the product. Because only dissolved drug penetrates the stratum corneum of intact skin (14), the precipitation of drug is expected to change bioavailability. Formulations that are prone to supersaturation, followed by unpredictable timing for precipitation, are rarely viable commercial products. Likewise, topical products formulated near API saturation that precipitate with relatively small drops in temperature need to rapidly redissolve upon storage at their labeled temperature range to be viable commercial products. Concerns about precipitation midway through stability of a material completely dissolved at product release are not limited to API. A good illustration of the preservative methylparaben precipitating out of a topical gel is provided in the specification and examples of US patent 8,053,427 (15).

Particle changes. If the drug substance is dispersed in the formulation as solid particles, particle size and content uniformity throughout the entire container/closure system will be two critical attributes for the topical drug product. Characterization of segregation and/or aggregation of particles will be necessary, in addition to demonstrating that no changes in the drug substance polymorph occur throughout the stability studies. Particle size of the drug substance throughout the shelf life of the topical product must be determined and may need to be controlled. For particles less than 10 microns, changes in particle size and/or morphology of suspended drugs in topical products are presumed to change bioavailability (14, 16).

Microbial contamination. It is important that products applied to the skin are not contaminated by bacteria or fungi and for this reason, topical products, especially products packaged in multiple-use containers, are usually preserved. Healthy skin provides a reasonably effective barrier against microbes, but this barrier is often compromised in skin conditions that are treated with topical products. Products applied to the face will eventually find their way into a patient’s eyes, which is another reason that even vehicle controls must be adequately preserved to assure patient safety. For topical products, passing United States Pharmacopeia (USP) <51> Antimicrobial Effectiveness Testing (AET) over the entire product shelf life is sufficient to assure that if contaminated, the product will not support growth and be a risk to the patient (17). AET testing assumes that incoming raw materials will not have significant lot-to-lot differences in the level of bacteria/fungi contaminating the API or excipients that are used to make the product.

pH. Most topical formulations will be adjusted to a specified pH at some point during processing. If the pH remains stable over the shelf-life of the product, then an appropriate control strategy can be put into place to keep pH as a very low risk, non-critical quality attribute. However, some actives degrade into weak acids (e.g., benzoyl peroxide degrading into benzoic acid) and if the product is not buffered (or insufficiently buffered), then the pH steadily drops over the shelf life of the product. If the active has pH-dependent solubility or a dissociation constant near the product pH, then it is likely that bioavailability may change with changing pH (8). The acid/base properties of some excipients can significantly impact the initial pH of the formulation. Lot-to-lot variability of excipients that can shift pH should be a risk mitigation focus for APIs that carry charge.

Assay and impurity tests. Assay tests that are specific, accurate, and precise are mandatory to quantify the amount of API present (per unit weight or volume) in the topical drug product. Likewise, impurity tests are required for specified impurities as justified by ICH Q3B (18) qualification threshold and unspecified impurities as justified by the identification threshold based on the maximum daily dose for the drug product (7). Excipients must be compatible with the API, and drug–excipient incompatibility is usually noted early in development and the formulation modified to assure an adequate shelf-life. A much more difficult problem is when trace level substances (e.g., catalysts, heavy metals, unreacted reagents) contained within an excipient are incompatible with the API. Degradation of the API may be rapid and limited by complete consumption of the trace levels of the excipient impurity. Usually this degradation of the activewill be viewed as a processing loss and be ignored (if less than 1%) or corrected by use of an overage. However, if this reactive trace excipient impurity has significant lot-to-lot variability or is not uniform throughout the excipient batch, then the drug product may risk occasional lots failing on stability.

Residual solvents and heavy metals. The drug product manufacturer will always be concerned about complying with USP General Chapter <467> Residual Solvents (19) and USP General Chapter <232> Elemental Impurities-Limits (20). The requirements include not exceeding limits for the finished drug product by controlling the elemental impurities and residual solvent of excipients. It should be noted that topical products may contain a significant amount of solvent (e.g., ethyl alcohol) and for these products, the solvent used is counted as an excipient, not a residual solvent (6).

Conclusion

The goal of Part I of this series is to familiarize the excipient supplier with some of the QbD concepts and terminology specifically related to topical pharmaceutical products. The pharmaceutical industry is embracing QbD for topical products for both NDA and ANDA products. With this understanding of QbD, it should be possible to build more effective partnerships between topical product development scientists and topical excipient vendors. QbD is truly the new paradigm in topical product development and is providing patients with more robust treatment options. Part II will propose reasonable customer expectations regarding excipient sample requests and specific information about excipients needed for the QbD approach.

References

1. FDA, Pharmaceutical CGMPs for the 21^st Century—A Risk-Based Approach. Final Report (Silver Spring, MD, September 2004).
2. ICH, ICH Harmonised Tripartite Guideline: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions Q4B, Step 4. (Geneva, Switzerland, Nov. 1, 2007)
3. ICH, ICH Harmonised Tripartite Guideline: Pharmaceutical Development Q8(R2) (Geneva, Switzerland, August 2009).  
4. ICH, ICH Harmonised Tripartite Guideline: Quality Risk ManagementQ9 (Geneva, Switzerland, Nov. 9, 2005).  
5. ICH, ICH Harmonised Tripartite Guideline: Pharmaceutical Quality System Q10 (Geneva, Switzerland, June 4, 2008). 
6. R.K. Chang et al. AAPS J. 15 (1) 41-52 (2013).
7. R.K. Chang et al. AAPS J 15 (3) 674-683 (2013).
8. Y.S.R. Krishnaiah et al. Int. J. Pharmaceutics 475 (1­­-2) 110-122 (2014).
9. H. Winkle, et al. Pharm. Tech. 33 (10) (2009).
10. FDA, Guidance for Industry Q8(R2) Pharmaceutical Development (Silver Spring, MD, November 2009).
11. FDA, Guidance for Industry Q9 Quality Risk Management. (Silver Spring, MD, June 2006).
12. ICH, Quality Implementation Working Group Points to Consider (R2) ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation. (Geneva, Switzerland, Dec. 6, 2011).
13. R.A. Lionberger et al. AAPS J. 10 (2) 268-276 (2008).
14. M.S. Roberts and K.A. Walters. The Relationship Between Structure and Barrier Function of Skin. Chapter 1 Dermal Absorption and Toxicity Assessment, M.S. Roberts and K.A. Walters, Eds. (Marcel Dekker, New York, 1998) pages 1-42.
15. J.C. Buge, K. Nadau-Fourcade, and C. Meunier. "Bromonidine gel composition," US Patent 8,053,427, Nov. 8, 2011.
16. A. Vogt et al., JID Symposium Proceedings 10 (3) 252-255 (2005).
17. USP, USP Chapter  <51>, "Antimicrobial Effectiveness Testing," USP29-NF24 (US Pharmacopeial Convention, Rockville, MD, 2005), p. 2499. 
18. ICH, ICH Harmonised Tripartite Guideline: Impurities in New Drug Products Q3B(R2) (Geneva, Switzerland, June 2, 2006).
19. USP, USP Chapter <467>, "Residual Solvents," USP37 (US Pharmacopeial Convention, Rockville, MD, 2011), https://hmc.usp.org/sites/default/files/documents/HMC/GCs-Pdfs/c467.pdf
20. USP, USP Chapter <232>, "Elemental Impurities—Limits," (US Pharmacopeial Convention, Rockville, MD, Feb. 1, 2013), www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/c232_final.pdf. 

About the Author

David W. Osborne is chief scientific officer and founder of Independent Derm Solutions, LLC, 4215 Creekside Court, Fort Collins, CO 80525,dosborne@independentdermsolutions.com. 

Article Details

Pharmaceutical Technology
Vol. 40, No. 10
Pages: 38–43

Citation

When referring to this article, please cite it as D. Osborne, "Impact of Quality by Design on Topical Product Excipient Suppliers, Part I: A Drug Manufacturer's Perspective," Pharmaceutical Technology 40 (10) 2016.

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