Excipient Variability: Causes, Identification, Control

The physical and chemical properties of an excipient can have an impact on the manufacture and performance of the pharmaceutical products. With regulators placing increasing emphasis on quality by design (QbD) in product development, the industry is now paying closer attention to the role of excipients in the formulation of drugs and the impact of excipient variability on the quality of the final drug product. Representatives of excipient development organizations addressed key aspects of excipient variability with Pharmaceutical Technology.

Participants of this roundtable discussion include Bernhard Fussnegger, global development and technical marketing, BASF Pharma Ingredients; Dora Meissner, regulatory manager and Rick Mutchler, president, BioSpectra; Carl Mroz, director--global regulatory affairs, Colorcon; True Rogers, R&D pharma technology leader, Dow Pharma and Food Solutions; and Ann Gray, market segment manager oral excipients, Evonik Pharma Polymers & Services.

Multiple causes of variabilityPharmTech: What are common sources of excipient variability?

Mroz (Colorcon): Excipients come from two main sources: natural or naturally derived excipients, such as corn or potato starch, and synthetic or semi-synthetic excipients, derived through chemical processing of a feedstock source. Variability can be due to the feedstock source, which may be the growing conditions in the case of naturally derived excipients, or chemical processing for synthetic or ‘semi-synthetic’ excipients.
Batch-to-batch variability of the same material results from the combination of variances in the feedstock, process technology, process parameters, operator actions, and even environmental conditions. When different manufacturers produce the same excipient, this can lead to variability through the manufacturing processes, such as batch versus continuous processing and on the scale and/or location of manufacturing.

Meissner (BioSpectra): Some common sources of excipient variability are inconsistent raw materials used during synthesis, inappropriate environmental conditions during manufacturing, packaging and storage, faulty or absent manufacturing controls, and skills/hygiene of operators handling and manufacturing the excipient. Additional sources of variability can be traced to manufacturing systems not designed for use to manufacture excipients and technology not designed for use to manufacture excipients. Multiple supply sources for raw materials with lack of equivalency can also lead to product variability. Further variability can be traced to lack of controls of in-process and finished goods during manufacturing stages.

Fussnegger (BASF): Product variability of excipients is mainly influenced by fluctuations in the specifications of starting materials. Critical are products derived from animal, vegetable, or mineral sources. Even seasonal and different regional provenance can have a remarkable impact. Also, variability of excipient properties is critically influenced by non-validated or manually performed production processes. The knowledge of critical product parameters and their link to the corresponding process parameters is key to help minimize fluctuations in excipient quality. Routinely maintained production equipment with well controlled and calibrated metering instruments will provide excipients with low variability.

Gray (Evonik): Raw materials and manufacturing processes are sources of excipient variability. Feedstock for naturally derived excipients can vary depending on species of crop, growing conditions, mining location, etc.  Higher natural feedstock variability can mean broader variation in functionalization, for example, the degree of substitution of natural polymers. The product specifications are often met by blending of batches.

In contrast, synthetic excipients are manufactured from synthetic substances and hence show limited risk of variability due to raw materials. Reliable functionality of synthetic polymers is integrated into the molecules by design and ensured through the use of predictable and tightly controlled conditions during manufacturing.

Rogers (Dow): One source of variability is the manufacturing process to produce the excipient. Another is the inherent measuring variability of analytical methods used to characterize properties, such as those listed on a certificate of analysis (CofA). Yet another is the variability in the raw materials needed to produce the excipient. For example, one of the key components of cellulose ethers is the cellulose raw material itself. No two trees look identically alike, so it is naturally expected that there is some inherent variability from lot to lot of cellulose raw material.

Impact of excipients on drug performancePharmTech: How significant is the impact of excipient variability on drug product performance?

Rogers (Dow): The excipient is often one of the key enablers of drug product performance. For example, the excipient may enable the dosage form to release the API over an extended time period (i.e., 12- or 24-h release). Chemical properties of the excipient, such as molecular weight and structure, can dictate modified-release performance. Physical properties, such as particle size and shape, can impact the formulation processes during drug product manufacture. Lot-to-lot variations in excipient properties might impact processability and performance of the resulting dosage form.

Gray (Evonik): The impact of excipient variability on drug product performance depends strongly on the function of the excipient in the drug product. Variability in a processing aid used in an immediate-release tablet, for example, may not affect drug product performance significantly. However, variability in a controlled-release polymer can, of course, strongly affect drug product performance. Examples of excipient properties that might affect manufacturability include viscosity, particle size, and flow properties; whereas parameters such as moisture content or impurities could possibly influence drug product stability, depending on the use and the API characteristics.

Mutchler (BioSpectra): Excipient variability significantly impacts the performance of the drug product as 70-80% of the drug product can be composed of excipients. Excipients with unrecognized variability used in pre-final dose manufacturing can lead to mistakenly spending significant resources on investigating pre-cursor variability when the real variability was introduced earlier in the process.
Examples of excipient properties that may affect drug product performance are often tied to specifications that do not fully recognize the true impurity risk from the site of manufacture. Lack of uniformity in product characteristics, such as particle size, bulk density, trace impurities, moisture, and likely contamination from unidentified solvents and undesired chemicals used at the manufacturing site, can adversely affect recognized or expected solubility, manufacturing, stability, and bioavailability.

Mroz (Colorcon): FDA has presented recalls due to variability of excipients, resulting in poor dissolution. Examples are:
Variation in coating--Zein NF (a natural polymer derived from corn) resulted in variability of immediate-release profile of a coated tablet
Softgel capsules as result of cross-linking short-chain aldehydes--the interaction with API-affected bioavailability.

Fussnegger (BASF): As medical products are precisely characterized in regulatory documents with validated production parameters and product characteristics, any variability of the excipient can have a detrimental influence on drug manufacture and drug efficacy. In this respect, particle size distribution, morphology, or the specific surface area of a given excipient--all non-compendial parameters--may influence the final dosage properties. Even a simple parameter such as the pH value of a dissolved or dispersed excipient can affect the release character of a formulated API.

Guidance, but no mandatory rules
PharmTech: What guidance do the United States Pharmacopeia and European Pharmacopeia provide on excipient performance and functionality-related characteristics (FRC)?

Meissner (BioSpectra): Chapter 1059 of USP; Excipient Performance suggests appropriate tests and specifications that ensure consistent and reliable performance should be added in a manner and at a level consistent with the risk level derived from a qualified assessment of the excipient. Additional specifications, even to those of existing monographs, should be added to reflect the required performance of the excipient when used in a drug formulation.

Chapter 5.15 of European Pharmacopoeia, Functionality-Related Characteristics of Excipients, in conjunction with the FRC section of each monograph, provides insight as to how the functionality of the excipients can be controlled and may require additional specifications based on the excipient’s critical role in a drug product formulation.

Mroz (Colorcon): The USP General Chapter <1059> on Excipient Performance provides guidance on physical and chemical properties along with general chapters that could be useful in characterizing excipient critical material attributes (CMA). Ph.Eur. has added to selected excipient monograph sections “Functionality-Related Characteristics of Excipients” which are non-mandatory sections linking material attributes with intended function.

Gray (Evonik): For the time being, pharmacopeial monographs, as one traditional way to control and define the quality of an excipient, provide no binding guidance for an excipient’s functionality or performance. However, there are several concepts in monograph development or modification to address these aspects. Existing examples include family monographs (Ph. Eur., e.g., Macrogols), functionality-related testing (Ph. Eur./USP-NF, e.g., magnesium stearate) and attributes of different articles by type differentiation (USP-NF; e.g., ammonio methacrylate copolymer, Type A/Type B-NF). Proposed ideas include flexible- and performance-based monographs (both Ph.Eur. and USP-NF). All of these concepts can contribute to express excipient functionalities from an accepted pharmacopeial perspective.

Rogers (Dow):USP and Ph. Eur. provide guidance on excipient definition and excipient safety, but provide little guidance on performance and functionality. These regulatory guidelines give manufacturers a set of boundaries within which to operate, while also providing flexibility to tailor solutions that may be required for a particularly sensitive formulation. Evaluation of excipient characteristics that impact the function of a drug product should be determined experimentally for each formulation and not dictated by pharmacopeial documents.

Fussnegger (BASF): USP intends to edit the General Chapter <1079> on excipient functionality. Ph.Eur. has already started to define FRCs in some excipient monographs. As these are non-mandatory parameters and very much dependent on the dosage form an excipient is formulated in, they need to be considered as guidance only. Information deducted from QbD experiments in the course of medical product development will provide the best feedback on tolerances of product parameters and their variability. Whether or not they are congruent with compendially defined FRCs has to been proven for each and every finished dosage form.

Identifying critical risksPharmTech: Not all excipients and not all properties of an excipient affect product quality and safety. How do you identify which ones are critical? What are the challenges in assessing the risk of excipient variability?

Fussnegger (BASF): Pharma companies are typically hesitant to share details on the exact use of excipients, especially in the early phase of projects. Exchanging information on the actual excipient application at an early stage is essential for the excipient manufacturer to identify parameters that can potentially influence the functionality of the drug product being developed. Risk assessment on the user and manufacturer side thus demands a mutual exchange of information on critical product properties and their acceptable and maintainable ranges.

Mutchler (BioSpectra): Critical properties are those that impact the chemical and physical properties of excipients and their end-use applications. Knowing the end use application of the excipient and its reactivity with other compounds will aid in identifying the critical quality and safety attributes to help eliminate negative impacts from excipient use. As excipients come closer to the ingredients found in the end product, the greater the need to identify them as critical. Challenges in assessing the risk of excipient variability are greatest when there is incomplete or mistaken communication or translation between the manufacturer and the user.

Mroz (Colorcon): A key is to link material attributes and process parameters to the drug product. Assessing the risk of excipient variability involves identifying which attribute or property has an impact on the performance of the finished dosage form and the extent of variation, then studying whether these influence performance or not. The concept of QbD is to understand variability, including excipients, to ensure the formulation is sufficiently robust to be able to withstand potential variability.

Risk assessment is a valuable science-based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CMAs.

Rogers (Dow): I have found that it is of paramount importance to tie drug product performance attributes back to both manufacturing process parameters and raw material properties. Doing this systematically enables one to hone in on the most critical process parameters and raw material attributes impacting processability and performance. Oftentimes, it is difficult to find raw materials exhibiting attributes at the edges of the specification ranges. Sound experimental design is essential for success. To address the challenges associated with QbD, excipient suppliers and drug product manufacturers should collaborate closely and earlier during the drug-product development process.

Gray (Evonik): Proper risk assessment requires detailed knowledge of the excipient functionality in the finished drug product. The significance of a parameter such as size distribution of controlled-release polymer particles is different depending on whether the polymer is dissolved in an organic solvent to prepare a coating or used as matrix former in direct compression. We use our extensive polymer and formulation know-how as a base for helping our customers understand the effects of excipient variability in standard applications. Furthermore, in cases where our products are used in non-standard, novel ways, we work together with our customers to tackle the challenge of risk assessment.