Applying QbD to Excipient Formulation and Development - Pharmaceutical Technology

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Applying QbD to Excipient Formulation and Development
A Technical Forum featuring representatives from Dow Chemical, ISP, and DMV-Fonterra Excipients. This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."

Pharmaceutical Technology
Issue 34, pp. s24-s29

Suppy-chain challenges

PharmTech: Supply-chain integrity for pharmaceutical ingredients is of great importance to the industry. In terms of excipient supply, how have supply-chain practices (e.g., audits, vendor selection, and qualification) evolved to meet this challenge?

Busch/Frazier (Dow): Dow has been a member of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) since its inception, and we use IPEC's excipient guidelines in the manufacture of our excipients. These guidelines include aspects concerning composition, stability, CoAs, quality agreements, good manufacturing practices, and notification of change practices.

At Dow, we also conduct regular, customer audits at our various excipient-manufacturing sites, done under the mantle of transparency, continuous improvement, and customer access. Regularly scheduled audits, including multiple customers, cuts down on the number of tailored audits required.

Our vendor selection is also quite rigorous. As a global supplier, we require our vendors to have globally acceptable capabilities. This requirement helps us to use recognized, global leaders that have the reach and technical expertise we require to support their products in our operations . In terms of qualifications in the last year, none of our suppliers have changed significantly.

Porter (ISP): Audits of ingredient suppliers are not new. It is likely, however, that audits have become more rigorous in recent years. In a similar vein, vendor selection and qualification practices have evolved over a number of years, and the requirements have become more rigorous over time.

One area receiving more attention lately is the use of third-party audits to verify whether excipient suppliers comply with suitable quality standards. Although excipient suppliers value audits as opportunities to improve quality practices, many suppliers have several hundred customers, and it is simply not practical for every or even most customers to conduct an audit. However, this is in conflict with regulatory and internal pharmaceutical company requirements. Thus, establishment and acceptance of third-party audits are starting to emerge.

In terms of maintaining security of the supply chain, pharmaceutical companies appear keen to ensure that more than one vendor is qualified for each and every raw material used.

Langridge (DFE): Audits increase annually. There is a desire among many companies to qualify more than one supplier of excipients in case of supply failure. This trend tends to imply that companies are starting to test specifications that encompass a range of suppliers rather than limit tests to a single supplier's specification.

Regulatory considerations

PharmTech: From an industry perspective, what would you identify as the key regulatory considerations with regard to excipient manufacture and use?

Busch/Frazier (Dow): Geographic and regional differences that need to be matched with a global selling proposition present challenges for excipient manufacturers, particularly in emerging geographies where customer requirements are quickly evolving to mimic Western standards. For example, many Indian companies are quickly changing to meet European standards. Other issues that are of importance include the need for regional regulatory expertise. An ever changing supplier-customer mix will make reputation more important.

The emergence of the IPEC Federation cannot be understated (see more details on the federation). The federation will coordinate and harmonize the activities of the various individual IPEC organizations. The relatively recent harmonization of the monographs between the US, Europe, and Japan for certain excipients such as hypromellose, has been a tremendous benefit to the industry as well. Harmonization will reduced redundant testing and make it much easier to provide products on a global scale. The IPEC Federation will similarly benefit the industry by issuing guidance documents that are global in nature and thereby prevent (or at least minimize) geographic variability.

With regard to any functionality guidance, in the United States functionality tests are part of the US Pharmacopeia general chapters. This location for such tests is critically important because excipients can be used in a variety of applications, each of which may have certain functional needs. The end user can select those tests appropriate to their application, and omit those tests that are not applicable. To require functionality testing in the monograph forces all tests to be run on the product, some of which may have no bearing on the performance of the excipient for its specific intended application. This extra testing causes unnecessary work for the excipient supplier and passes additional costs to the drug manufacturer.

If functionality cannot be predicted by any of the various tests required by the monograph, additional tests that can predict performance in the specific application can be jointly developed by the excipient supplier and user through a quality agreement.

Porter (ISP): Although not a recent event, the requirement that excipient manufactures comply with some semblance of good manufacturing practice has become more rigorous over time. This requirement has led excipient manufacturers to adopt many of the practices that have long-been used by pharmaceutical manufacturers (e.g., implementation of change-control procedures, conducting process validation programs during process start-up and when significant process changes are to be implemented or when manufacture of a product is moving to a different manufacturing site).

Excipient functionality is a thorny subject because it requires that meaningful functionality tests are identified—these tests also must be simple and inexpensive to implement and operate. The result, quite often, is that the test has little resemblance to a true functionality test, but rather produces data that hint at, rather than confirm, excipient functionality.

Langridge (DFE): There is more desire to understand the role of excipient properties from regulators and industry. The question is whether the 'functionality' aspects of excipients should be addressed officially in pharmacopeias or on a case-by-case basis (e.g., in a new drug application or other regulatory submission). Key properties of an excipient for function in one formulation may be irrelevant in another formulation, even if the dosage form is the same. Therefore, official measures of functionality can only be framed in the very broadest terms. In the European Pharmacopoeia, some functionality-related characteristics (FRCs) are marked as nonmandatory, but this listing does not prevent excipient users from expecting these to be certified and controlled, even though the FRC may have no effect on the formulation.

To take a previous example, amorphous content is important in the compaction of spray-dried lactose, but it may not be of consequence if the tablet formulation contains other compactable components. To take a second example, the development of two monographs for lactose for inhalation may well result in a loss of functionality for some users because the extra limitations of the monographs restrict the lactose choices available to dry-powder inhaler formulators.

The downside of determining excipient functionality on a case-by-case basis is that for some products, this can lead to the development of tailored grades for different customer products, which may be a huge hurdle for some excipient manufacturers. Those excipient manufacturers willing to tailor grades will expect, and indeed require, substantially higher prices from the purchaser. In the end, it is the purchaser who must decide whether the cost of a tailored excipient is worth the security it brings for their product.


1. J. L'Hote-Gaston et al., Pharm. Technol. 33 (12), 36–41 (2009).


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