Dealing With Complexity in Excipients and Formulations

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After years of taking excipients for granted, the pharmaceutical industry is beginning to realize just how complex these “fillers,” and the products into which they are formulated, can be. The physicist Kim Christensen has noted the following as signs of the complexity of any system (1): 

• Repeated application of simple rules

• Many degrees of freedom (i.e., many variables that are free to vary in a dynamic system)

• Emergent behavior that has not been encoded in the rules.

In formulation and product development, the industry must currently deal with the following:

• Pharmacopoeial compliance

• The variability (degrees of freedom) found in both excipients and finished products

• Special cause variation in finished products, independent of excipient compliance.

Compendial specifications are not enough

Pharmaceutical manufacturers today contend with such complexity in the face of increasing analytical capability and regulatory pressure for better quality. The FDA has stated that pharmacopeial compliance is a necessary, but insufficient, prerequisite for pharmaceutical quality (2):

“When a USP or National Formulary (NF) monograph material is used, the associated specifications may not always provide adequate assurance with regard to the assay, quality, or purity of the material or its performance in the drug product. In these cases, monograph specifications should be supplemented with appropriate controls (e.g., particle size distribution, crystal forms, amorphous content, foreign particulates) to ensure batch-to-batch reproducibility of these components.”

Simply citing pharmacopoeial compliance for excipients under the Specifications section of the Chemical Manufacturing and Controls (CMC) portion of a new drug application may result in requests for justification of reliance on compendial specifications.

One of the major degrees of freedom in excipients is polydispersity, in terms of their molecular weight, composition, and particle size distribution. Additional degrees of freedom arise from the raw materials (including additives) and processes used to manufacture the excipients.

Sources of variability

Many common excipients are continuously manufactured in high volumes, so the variability behind the results on the certificate of analysis is an additional degree of freedom. Any attributes not specified by the monograph also represent degrees of freedom.

All of these degrees of freedom illustrate why compliance alone cannot determine whether a given excipient will be fit for purpose in a particular application. The products into which the excipients are formulated also have multiple degrees of freedom.

Paradoxically, attempts to reduce finished product variability, by fixing the processes and formulas, have been counterproductive, since raw material variability can feed forward in a rigid system and affect finished-product quality. Any design or control strategy that does not have compensatory mechanisms to deal with raw material variability is at higher risk from the impact of excipient variability.

Complex systems, such as pharmaceutical products, may exist in multiple states. The transition from one state to another is known as a criticality.

Properties or performance on one side of the transition may not allow manufacturers to predict performance on the other side. Such critical transitions are another degree of freedom, and are also known as latent conditions because their existence is unknown to the designer.

Conflicting requirements

The most common sources of criticalities in pharmaceutical systems are percolation effects, or conflicting technological requirements.  Percolation effects abound in powder mixing and tabletting physics. Overgranulation is an example of conflicting technological objectives. If the minimum effective granulation level is too close to the level that causes overgranulation, a criticality will result.

If minor excipient variability, possibly a known attribute within its norms of variability, interacts with a finished product criticality, a disproportionate, non-linear response may result, such as an out-of-specification excursion. Not all sources of critical variability will be identified at the time of filing, and excipients can cause special cause variation in finished product quality. Such variation is unanticipated, outside the historical experience base, and inherently unpredictable, even probabilistically.

Traditionally, excipients have been categorized as critical or non-critical.  Critics have said that this approach to classifying process parameters and quality attributes is overly simplistic, and does not adequately reflect science and risk-based thinking (3).

A better approach is to divide the excipients into design-critical or not design-critical. Design-critical implies a direct cause and effect on finished product performance, where the level of the excipient is titrated above a minimum, or to an optimal level, for specific performance in the finished product. Examples would be disintegrants, suspending agents, or the rate-controlling polymer in a controlled release matrix. Variability in such excipients can directly impact finished product performance.

Impact of the non-critical

By definition, “non-critical” excipients and their variability have no observed effect on the critical quality attributes of the finished product during development. However, just because there is no evidence of a problem does not mean there is no problem. Because there is no reason to expect an impact, a null finding is inconclusive.

History is full of examples in which “non-critical” excipients have become critical during a product lifecycle, often due to their interaction with finished product criticalities. Because impact is based on variability plus drift plus criticality, the impact of “non-critical” excipients is indirect.

Better change control needed

Indirect impact from “non-critical” excipients highlights the weakness of conventional change control. A pharmaceutical product is subject to the cumulative effect of multiple changes throughout its lifecycle.

Univariate change control observes no impact from each individual change, but may not detect drift due to the cumulative effect of the multiple changes. Ultimately, one change too many triggers a criticality correlating with an excipient variability. It is important to note that the excipient variability has not caused the problem, but is now merely coincident with the criticality. Continuous multivariate monitoring of the finished product is required to detect product drift.

Accounting for product drift

Left unchecked, product drift may adversely affect process capability, leading to out-of-trend or out-of- specification results. If a criticality is triggered, there may be a non-linear, disproportionate impact invalidating models or control logic. The potential impact could become more significant with the move to continuous processing and real-time release. It becomes more difficult to demonstrate control. 

A well-thought-out control strategy is the only way to deal with so many excipient-related degrees of freedom. The application of materials science and risk-management principles will drive the need for more and better data on excipient properties and performance. This will require closer collaboration between suppliers of excipients and their customers.

Ranging studies may be useful in identifying the sensitivity to excipient variability vs level of incorporation. Products with an excipient close to the minimum effective level will be more sensitive to variability in that excipient.

Design of experiments should focus on design-critical excipients, but the control strategy must cover all excipients and related application-specific failure modes. Good designs build in compensatory flexibility. Usually, this is in terms of process parameters, but future designs could focus on formulation.

Access to supplier data going beyond the certificate of analysis is needed in order to understand supplier process capability and to enable continuous multivariate monitoring. Beause product drift and criticalities cannot be verified experimentally, it is up to users and suppliers to work together on due diligence. Such collaboration provides the best, lowest risk way for incorporating excipients into the product and process design.

References

1. K. Christensen and N. Moloney, Complexity and Criticality, Imperial College Press, London, 2005.
2. FDA Guidance for Industry, Nasal Spray, Inhalation Solution, Suspension and Spray Dried Products,” (FDA, July 2002).
3. D. O’Keefe et al., “A Spectrum of Importance: Challenging the Concept of Critical/Non-Critical in Qualification and Validation Activities,” Institute of Validation Technology, ivtnetwork.com, Feb. 29, 2016. Retrieved July 26, 2016.

About the Author

Brian Carlin is director of open innovation at FMC Corp.

Article Details

Pharmaceutical Technology
Vol. 40
APIs, Excipients, and Manufacturing Supplement
September 2016
Pages: s12–s14

Citation

When referring to this article, please cite it as B. Carlin, " Dealing With Complexity in Excipients and Formulations," APIs, Excipients, and Manufacturing supplement to Pharmaceutical Technology 40, 2016.