Excipient Selection and Supply for Complex Drug Products

What are Excipients?

The FDA describes an excipient as an inactive ingredient intentionally added to therapeutic and diagnostic products, which is not intended to exert therapeutic effects at the intended dosage, but which may act to improve product delivery (e.g., enhance absorption or control release of the drug substance). Excipients are highly diverse and serve a critical role in optimizing drug delivery. According to recent figures, the pharma excipients market will reach approximately USD 9.78 Billion by 2025, growing at a CAGR of approximately 6% from 2018 to 2025¹.

Examples of excipients that are used in complex drug products include:

• Release Modifiers: often polymers (e.g., PLGA, TPU, silicone) that enable long-acting drug delivery systems such as implants and depot injections
• Suspending Agents/Viscosity Modifiers: materials that increase viscosity to form sterile or non-sterile semi-solids and oral/ophthalmic suspensions (e.g., Carbopol^® carbomers)
• Solubility/Bioavailability Enhancers: polymers that allow the formation of amorphous solid dispersions/solutions through spray drying, extrusion, and granulation processes (e.g., HPMC-AS, PVP, PEG)

In traditional oral solid dosage forms, many excipients are used as bulking agents, fillers, and binders to form a pill or improve direct compression processes. However, for complex drug products, excipients often play a functional role in the dosage form, improving or modifying the delivery of an active pharmaceutical ingredient (API). For example, the release of API from long-acting PLGA microspheres is highly dependent on the chemical composition of the PLGA polymer and its molecular weight.

Whatever the dosage form, selecting the correct excipients is critical for assuring the desired therapeutic effect for a patient.

Demand for novel excipients is driven by efforts to develop differentiated drug products, including:

• Novel treatments for chronic diseases
• Repurposing of drugs for new uses or for new routes of administration
• The growth of alternative regulatory options to develop new drug products (e.g., 505(b)(2) drug products)
• New drug delivery platforms

In addition to enabling differentiated products, drug developers are seeking innovative materials that address common challenges in the drug development pipeline, such as poor solubility and bioavailability. There is also a growing desire for extended-release products, improved manufacturing efficiency, and general formulation enhancement.

So, what factors must be considered when selecting an excipient?

Key Considerations for Excipient Selection

Quality

When it comes to excipient quality, it should be noted that there is no “separate” excipient manufacturing industry. Unlike APIs, which are often produced by pharmaceutical manufacturers under the appropriate Good Manufacturing Practices (GMP), excipients are generally produced and packaged by chemical companies. Many materials used as excipients have applications outside of pharmaceuticals, such as food additives, cosmetics, or industrial products. Thus, environmental conditions, equipment, and operational techniques employed in excipient manufacture are often those of the chemical industry rather than those of the pharmaceutical industry.  It should be recognized that poor quality excipients can result in failure during manufacturing, ineffective drug products, and compromised patient safety. Typically, patients consume significantly more excipients than active ingredients in drug products, therefore quality is critical. It is important that drug manufacturers source from high-quality suppliers that have compliance systems and processes in place to ensure the product can be consistently manufactured to meet quality and performance specifications and is safe for the intended use. There are many examples of adulterated or misbranded raw materials that have caused risk to the patient when ingredients not designed and manufactured for pharmaceutical use are included in medicinal products.

A poor-quality excipient can prevent a drug product from meeting critical quality (CQAs) and performance attributes. Such compromises in quality will negatively impact the delivery of an API and ultimately affect the health of a patient.

When sourcing an excipient material, it’s important to assure that the quality is appropriate for pharmaceutical use and the supplier understands the industry and its safety standards. Materials used in drug products should be qualified and include specifications appropriate for intended use. Compliance with a compendial monograph like the United States Pharmacopoeia (USP) or European Pharmacopoeia (EP) further indicates quality appropriate for use in drug products. It should be noted that not all excipients have a compendial monograph, and irrespective of whether there is a monograph or not, it is the responsibility of the drug manufacturer to ensure that they are using excipients from a qualified supplier and that the excipient is safe for intended use.

There have been cases of raw materials not manufactured for use in drug products that have caused serious problems for patients, including allergic reactions and even death. For example, in 1995, tainted acetaminophen syrups in Haiti were linked to an outbreak of renal failure that killed more than 80 Haitian children. The syrups were sweetened with imported glycerin contaminated with diethylene glycol (DEG), a potent nephrotoxin and hepatotoxin².

GMP Manufacturing

The quality of excipients is critical to assuring the safety, quality, and efficacy of medicines. As discussed earlier, excipient functionality in drug products may range from use as a filler to imparting stability and influencing drug release. Therefore, applying appropriate GMP principles to manufacturing of excipients is essential.

Increasingly, users of excipients are required by global regulatory authorities to assure patient safety through the evaluation of risks and application of suitable GMP to the manufacture and supply of each excipient. While it is recognized that excipients should be manufactured under GMP conditions, they encompass such a wide range of materials that it’s difficult to define best practices and have clear guidance in place. APIs have a separate set of GMP guidelines which may not apply to excipients. To address these challenges, the excipients industry came together to form the International Pharmaceutical Excipient Council (IPEC), of which Lubrizol is a member. This consortium of excipients manufacturers, users, and distributors has produced guides on industry best practices for excipient manufacturers that cover GMP standards, Good Distribution Practices (GDP), and quality assessments. The IPEC GMP guide proposes GMPs appropriate for the manufacture of excipients and is a joint initiative between IPEC and the Pharmaceutical Quality Group (PQG). It was updated in 2017 and first published in 2006, incorporating the IPEC Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients 2001 with the PQG’s PS 9100:2002 Pharmaceutical Excipients.

More recently, other third-party certification programs have emerged, such as the EXCiPACT certificate and ANSI 363: Good Manufacturing Practices (GMP) for Pharmaceutical Excipients. These auditing programs enable companies to verify their compliance to IPEC-GMP guidelines for excipient manufacturing.

The quality of excipients is critical to assuring the safety, quality, and efficacy of medicines. Excipient functionality in drug products may range from use as a filler to imparting stability and influencing drug release. Therefore, applying appropriate GMP principles to manufacturing of excipients is essential.

Safety

An inactive ingredient is any component of a drug product other than the active ingredient and should be safe at the intended use levels in the drug product.  Currently, there is no separate regulatory pathway for safety evaluation or approval of excipients. Excipients are reviewed only as part of a drug product application.

The FDA has a guidance document on evaluating the safety of excipients for pharmaceutical products: Guidance for Industry for Non-Clinical Studies for the Safety Evaluation of Pharmaceutical Excipients. In this guidance, FDA has recognized that existing human data for some excipients can substitute for certain non-clinical safety data, and an excipient with documented prior human exposure under circumstances relevant to the proposed use may not require evaluation in the full battery of toxicology studies outlined in the guidance. For example, the FDA will continue to consider factors such as use in previously approved products or generally-recognized-as-safe (GRAS) status as a direct food additive. Under some circumstances (e.g., similar route of administration, level of exposure, patient population, and duration of exposure), experience associated with the prior use may adequately qualify an excipient. However, this guide is now more than 15 years old and IPEC is currently working on updating and issuing a new safety guide.

Ultimate safety responsibility sits with the drug manufacturer, who must ensure that the excipient is safe for intended use.

API-Excipient Compatibility

Excipients introduce several benefits to drug products, but developers must also be aware of unintended interactions between APIs and excipients. These interactions can affect both the physical and chemical properties of the drug, resulting in reduced therapeutic efficacy or physical stability. Several analytical tools may be needed to evaluate compatibility, including

• Separation and Quantitation Methods: Provide chemical identity and stability information for both the API and excipients. Examples include high-performance liquid chromatography (HPLC), gas chromatography (GC), mass spectrometry (MS), size-exclusion chromatography (SEC), and gel electrophoresis.
• Physical Characterization Methods: Provide information on interactions that may change the solid-state form of a drug or alter physical properties of the drug product. Examples include laser diffraction (for particle size analysis), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC).
• In vitro Release Methods: Provide a measure of drug release from the product, allowing developers to evaluate consistency of release from different formulations. Examples include dissolution and in vitro release testing using USP Apparatuses.

Using a range of analytical tools, drug product developers can ensure that the safety, stability, and therapeutic efficacy of their products are not negatively impacted by their choice of excipients. CDMOs should also possess the analytical capabilities to carry out these assessments during drug product development and manufacturing.

What Should You Look for in an Excipient Supplier?

Drug product manufacturers are highly dependent on excipient manufacturers to provide materials that are uniform in chemical and physical characteristics. As a general guide, excipient suppliers should provide quality products with clear specifications and be knowledgeable about the quality and product consistency requirements in the pharmaceutical industry.

For drug product manufacturers, one of the main concerns is the level of uniformity in an excipient’s chemical and physical characteristics. There must be a high level of batch-to-batch consistency from a supplier, as variability could affect the drug product. Excipient manufacturers who adhere to GMP manufacturing principles have good control over specifications and maintain quality over time. They also have change notification plans in place to ensure customers are notified of significant changes to excipient manufacturing.

Excipient Information Packages

In addition to self-certification or third-party certificates showing adherence to GMP guidelines, many suppliers, including Lubrizol, generate an excipient information package which includes key information on quality, regulatory status, material specifications, change management, physical/chemical attributes, and chemical composition.

Typical excipient information packages contain:

• Quality compliance information
• Regulatory status of excipients
• Manufacturing process information
• Site and supply chain security information
• Safety statements (e.g., animal derived materials statement)
• Technical information on functional performance
• Stability information for transportation and storage

Drug Master Files

Much of the information on manufacturing processes and composition of excipients is generally confidential and, as such, manufacturers of excipients are hesitant to share this information with customers. Drug Master Files (DMFs) enable excipient suppliers to share this confidential and business proprietary information with the U.S. FDA through a controlled access system. Excipient suppliers may then grant the FDA access to their DMFs for regulatory review to support individual drug applications without having to reveal confidential information to the drug product manufacturer directly.

There is no regulatory requirement to establish an excipient DMF in the U.S., and the requirements for sharing confidential excipient information vary by region. For example, China has recently instituted submission of excipient dossiers which are similar to DMFs. The information in these dossiers is reviewed as part of the drug application. Europe, on the other hand, does not have a mechanism for submission of excipient DMFs.

If you are interested in learning more about best practices for establishing excipient DMFs, you can refer to the IPEC DMF Guide.

How Can an Excipient Supplier Help a Formulator Adhere to QBD Principles?

Quality by Design (QbD) is an approach to designing and developing formulations and manufacturing processes to provide optimum product quality. It focuses on understanding and controlling the formulation and manufacturing process variables that affect the quality of the drug product.

QbD begins with a pre-formulation assessment where variables such as excipient compatibility are measured. The process continues with the development of a drug product having the required performance characteristics to meet the expectations of the developer, regulatory agency, patient, or caregiver.

When executed correctly, QbD leads to an understanding of the Design Space – the range of input variables within which the process can operate and still produce an acceptable drug product. These input variables include raw material/excipient specifications as well as equipment operating parameters.

The Role of Excipients in Drug Product Development

An excipient supplier should disclose enough CMC information on their material so that the drug product manufacturer can assess the quality and consistency of the excipient and develop a pharmaceutical product using QbD concepts.

Generally, the excipient manufacturer has very limited information on drug product development and how the excipient is being used in formulation. This limits the support and information that an excipient manufacturer can provide to their customer. It is therefore important for the drug product manufacturer to disclose enough details of the intended formulation so that the excipient supplier can provide material information to help with robust design of the drug product.

An experienced CDMO may also be able to provide support for excipient selection based on prior experience and/or relationships with excipient suppliers.

During the development process, testing is performed on multiple excipient lots to assure that design space is robust enough to accommodate variability in critical excipient attributes while meeting the target product profile for the drug product.

Conclusion

Excipient selection, including qualification of the supplier, is critical to ensuring the safety and efficacy of your formulation. A high-quality excipient can enable a drug product to achieve a desired therapeutic effect and reach commercial success. But inappropriate or adulterated materials may lead to quality, safety, and performance failures that hinder drug product development.

Regardless of which excipients or suppliers you are using, it is critical to identify companies who understand how to control quality and safety of excipients with the ultimate goal of ensuring patient safety. A good excipient supplier will contribute to your development process and enable success with robust quality systems, appropriate data, and meaningful contributions to QbD processes. And a good CDMO understands these critical aspects of excipient supply, establishing relationships with companies that can appropriately support their clients’ projects.

As a long-time excipient supplier and CDMO, Lubrizol Life Science Health understands excipient selection and will help you identify the right materials and formulation approaches to achieve success.

Learn more about our excipients portfolio, and start your project today!

References

1. Pharmaceutical Excipients Market by Type, Functionality, Formulation, Regions, Industry Analysis, Size, Share, Growth, Trends, and Forecast 2018 to 2025 – Fior Markets.
2. Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry | Wiley.

Authors: Meera Raghuram and Nick DiFranco