Excipient manufacture and quality control

Unlike the unit operations in pharmaceutical manufacturing, which are primarily batch-oriented, manufacture of excipients often employs continuous processing. An excipient batch or lot number may simply represent a defined period of time, rather than a discrete batch, with production quantities into the hundreds of tons. A Certificate of Analysis result provides a composite or average figure, and the supplier may have a much higher frequency of in-process testing on certain specification parameters. Access to such "raw" data will afford more meaningful correlations between supplier raw-material variability and the variability in CQAs of the user's finished products. Sharing such data will depend on the establishment of good supplier-user communications and trust. In the future, this information-sharing could be part of a supply or quality agreement, or a separate "QbD agreement." If necessary, relevant information could also be supplied under a specific, confidential disclosure agreement.

Requesting excipient samples at the extremes of specification for continuously produced materials is a problem. Driving a continuous process on the edge of specification means that half of the output will be out of specification. Understanding the raw-material variability in terms of the supplier's process capability greatly facilitates integration of materials understanding and process engineering (user and supplier). In a QbD universe, should we be looking to obtain materials at the extremes of specification when it is possible to use other means to establish a relevant design space? As discussed in the previous section, industry can use alternate grades, blends of grades, quantitative changes in excipient level, and fractionation to establish a design space.

One aspect of excipients that is not well understood is excipient composition. Most excipients work because they are not "pure" materials. By accident or intention, they are, in effect, mixtures, and the other components often play a significant role in the functional performance of an excipient. Unfortunately, industry does not know enough about the composition of any excipient to state with certainty which minor components are necessary for functionality in a particular application. These minor components are not "impurities" as we might understand impurities in the context of an API. Rather, these minor components of an excipient may actually be necessary for optimum functionality.

For example, despite the hydrophobic nature of magnesium stearate, its functionality as a lubricant depends on the water of crystallization. Water situated between oriented fatty acid chains facilitates shear, and the anhydrate is less effective as a lubricant (5, 6).

Dibasic calcium phosphate dihydrate (DCP) provides another example. The coarse grade of DCP is used in the formulation of tablets by direct compression. During the compaction process, DCP deforms via brittle fracture. It is possible to manufacture very pure DCP with a very low level of ionic "impurities" using precipitated calcium sources and so-called "green" phosphoric acid. Unfortunately, DCP prepared in this way does not provide adequate performance in direct compression because of a lower fragmentation propensity. In this case, foreign ions are required for optimum performance. Their incorporation into the crystal lattice disrupts the lattice structure and causes defects that facilitate brittle fracture. The highly purified material does not have sufficient lattice defects to fracture adequately during compaction, and the resulting tablets are much weaker.

Building in flexibility

Standardization of functionality, as practiced by other industries, offers lessons for QbD. Rather than focusing on the extremes of specification for selected raw-material parameters, it may be possible to bracket the specific excipient with complementary grades or materials. For example, the particle-size distribution of mcc is the basis of several grades, and particle size may be of importance in many applications. If substituting some or all of one mcc grade in your formulation (e.g., 100 µm) with other size grades (e.g., 50µm or 200µm) causes no unanticipated problems (other than flow), then the design space will be wider than the particle-size limits for the 100 µm grade. This bracketing example is one approach to constructing a design space during development, but the approach also can be incorporated into the formulation. Incorporation of complementary grades or materials builds in the necessary flexibility for continuous improvement throughout the product life cycle.

Not every aspect of the product and process can be optimized before launch. More than 95% of development formulations are never likely to be commercialized because of clinical or safety failures during development. For this reason, most commercial-product formulations are not developed until Phase II clinical development is nearing completion. Given that commercial formulations are developed relatively late during clinical development, many will not have been fully optimized when they are launched. Limited availability of the API during development and other considerations may afford only a 3- to 4-sigma level of operational excellence at launch. To achieve 6-sigma operational excellence requires the ongoing analysis of manufactured product and raw-material statistics to identify and control subtle raw-material contributions. These contributions may not have been identified at launch, or may have arisen subsequently. Raw-material contributions to finished-product variability should be minimized using proper evaluation of the design space during development, but they will be of greater significance to subsequent operational-excellence programs post-launch because under QbD, the product is continuously improved.

Building formulation flexibility into the development process will pay great dividends by allowing continuous improvement, complementing process flexibility and raw-material specification options. Ultimately, continuous production may be possible. A smooth continuous improvement in quality and scale is likely to become even more important with the trend of pharmaceutical blockbusters becomingmore progressive or incremental in life-cycle growth. Formulation flexibility, in which compensatory quantitative adjustments in excipient levels have been included in the design will protect against both short-term raw-material variability and long-term changes due to material supply or increased operational-excellence requirements.

Brian Carlin, MRPharmS, MRSC CChem, is director of open innovation at FMC BioPolymer in Princeton, NJ, and chairman of the IPEC–Americas QbD Commitee, brian.carlin@fmc.com
. R. Christian Moreton is vice-president of pharmaceutical sciences FinnBrit Consulting in Cambridge, MA, and a member of the Pharmaceutical Technology Editorial Advisory Board.

References

1. FDA, Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach (Rockville, MD, Aug. 2002).

2. ICH, ICH Q8(R2) Pharmaceutical Development, Step 4 Version (Aug. 2009).

3. G.E. Amidon et al., Pharm. Forum 33 (6), 1311–1323 (2007).

4. <1059> Excipient Performance," Pharm. Forum 35 (5), 1228–1250 (2009).

5. Y. Wada and T. Matsubara, Powder Tech. 78 (1994) p. 109.

6. K.D. Ertel and J.D. Carstensen, J. Pharm. Sci. 77 (1988) p. 625.