Securing Each Step
Excipients Manufacturers Adhere to Standards and Goals
Like nearly all aspects of public and private business, healthcare management organizations and national governments are feeling price pressure, and many look to mitigate this by saving money when it comes to drugs. This pressure gets passed along the value chain to the manufacturers of excipients, who strive to provide the highest-quality products to their customers in a world where the regulatory framework is unclear. Brandi Schuster asked some of this year's CPhI exhibitors the following questions:
- What do you consider to be the most pressing issues in excipients right now?
- What are the current trends and requirements from pharma manufacturers and formulators?
- What is your opinion on GMP for pharmaceutical excipients?
- What is your strategy for competing with excipients from the East?
B. Fritzsching (Beneo-Palatinit): There is an increasing cost-sensitivity within the pharmaceutical industry. While costs of clinical studies, regulation and quality assurance have been increasing over time, healthcare management organizations and governmental bodies are urged more and more to save money when buying drugs. As a consequence also excipients - particularly commodity standard excipients - are under price pressure in all segments of the industry.
Pharmacopeial monographs and drug regulations are lacking harmonization resulting in different requirements and various testing procedures requested by the European Directorate for the Quality of Medicines & Healthcare; the United States Pharmacopeia-National Formulary; and Japanese Pharmacopoeia-Japanese Pharmaceutical Excipients monographs. A single ingredient can only be approved in different regions around the world after it has fulfilled all of them. Although being essential, such a variety of procedures causes extra cost as well as hurdles for market growth.
B. Freiberg (Merck): As I see it, two requirements are particularly strong right now: functional excipients and risk mitigation.
Functional excipients can extend profitability and boost the efficacy of existing products by tailoring them more closely to customer needs. Pharmaceutical companies are recognizing the value of excipients more than ever, particularly when it comes to physical characteristics of increasing the flowability and compassibility of the tableting blend. Other characteristics of the drug such as efficiency, safety, stability and storage are also supported by using the right excipient. For example, new coating and disintegrant formulations can provide gradual release of active ingredients. That's a key product differentiator - to that effect, demand is growing fast.
Risk mitigation, of course, is more important than ever before. We still have no EU guidelines for excipients, so the best policy for manufacturers is to source supplies from a company with a good reputation for quality. That's the only way to get the consistent purity they need -plus, of course, fast, secure and reliable deliveries. At Merck, we secure every step along the entire process chain - we audit our suppliers stringently and repeatedly, and we only work with companies who share our standards and goals.
D. Pearson (Novozymes): Pharmaceutical manufacturers and formulation scientists strive to achieve optimal, robust drug dosage forms through the use of well-characterized excipients. Excipient choice can influence development timelines and acceptance of final drug products, thus influencing costs along the entire product lifecycle.
Required characteristics that determine excipient selection include functionality; material quality; product consistency (preferably through GMP manufacture); safety; regulatory compliance; secure sourcing; and cost. Raw materials derived from animal sources have also become a concern for formulation scientist due to risk of contamination of the final drug product with animal-derived adventitious agents.
The International Pharmaceutical Excipients Council Europe (IPEC) believes that along with manufacture to GMP principles, the availability of a drug master file (DMF) is critical to demonstrate the safety and efficacy of a new excipient. Currently in Europe, there is no such master file system in place for "novel excipients" that restricts excipient manufacturers' confidentiality due to lack of protection of intellectual property, as there is no option but to provide the master file-type information to the excipient user. As a consequence, few new excipients may be introduced, limiting European patient's access to improved medicines and placing Europe at a competitive disadvantage.
B. Fritzsching (Beneo-Palatinit): Under the light of drug development and excipient costs, the industry is looking for more highly functional excipients that fulfill different needs: They should help to reduce development times as well as production and formulation costs. Also they should be in accordance to all regulatory and quality requirements as well as available around the globe.
Since these excipients may also play an important role in the drug effectiveness as well as the safety and storage stability of the drug product, they are interesting to all segments. With special focus on over-the-counter drugs but also standard generics, highly functional excipients help to improve formulations by providing functionalities which had not been offered by the excipients used in the original formulations: The possibility to reformulate a drug into a different, faster acting dosage form (e.g. from tablet to sachets for direct oral application) or the opportunity to reduce the tablet size by using a filler-binder diluent excipient such as galenIQ (pharmaceutical grade isomalt from Beneo-Palatinit) are just two examples.
B. Fritzsching (Beneo-Palatinit): Pharmaceutical companies are obligated to secure the safety of their drug products in order to protect the patient. A traceability of all excipients and manufacturing steps is substantial. We regard the manufacturing of our excipient range galenIQ under cGMP standards as mandatory and therefore have been producing galenIQ under these standards since the very beginning.
Moreover, as a member of the International Pharmaceutical Excipients Council (IPEC), we are following the IPEC-PQG (Pharmaceutical Quality Group) cGMP guidelines for pharmaceutical excipients, as we are deeply convinced that these guidelines help to increase and maintain safety within the market.
B. Freiberg (Merck): As a quality-oriented company, Merck is fully committed to GMP. That's why we made a significant investment in our brand-new GMP plant in Darmstadt, Germany. The entire facility is designed to ensure the highest possible standards of quality and safety. And with three production lines, we're confident we can keep pace with demand for years to come.
D. Pearson (Novozymes): The manufacture of excipients according to GMP principles is critical to assure safety, quality and consistency not only of the excipients but also the final drug product. GMP is a requirement for almost every component of the drug, including the API and packaging materials.
The current lack of requirements for GMP principles to be applied to the manufacture of excipients seems to be counter-intuitive with the GMP requirements for APIs, as excipients can often make up a greater constituent of the final drug product.
Concerns over contamination of the drug products with viruses or transmissible encephalopathies (TSE) and the risk of substitution or contamination of the excipient with erroneous material have seen a push toward GMP requirements for excipients. Recently, the International Conference on Harmonization GMP standard ICH/Q7A4. Directive 2004/27/EC specifically mandated the implementation of GMP for "certain excipients" including, excipients prepared from materials derived from a TSE-relevant animal species and excipients derived from animal sourced material.
Manufacturing according to GMP principles ensures batch to batch consistency at the highest quality standard. Novozymes is committed to product safety and quality and therefore applies GMP principles in the manufacture of their excipient products.
B. Fritzsching (Beneo-Palatinit): There might be nothing wrong with many excipients from the East. Over time, most excipient suppliers from the East will meet all standards and requirements, since the market demands strict implementation of GMP standards.
However, it not just the excipient as such that makes the difference; it is the continuous improvement of services and trustful excipient functionality, high quality standards, IP protection and service package which makes an excipient supplier superior. This is in particular true for multifunctional excipients.
B. Freiberg (Merck): Simple: Instead of importing low-grade ingredients, we export our own high standards instead. Take China, for instance: Their own exports may not always be of the finest quality, yet when it comes to excipients, the standards they set for the domestic market are surprisingly strict. In fact, they are as equally demanding as in the West.
D. Pearson (Novozymes): Over recent years, there have been concerns regarding the quality and safety of excipients manufactured in China.
Novozymes has over 20 years experience in operating facilities in China, being the first Western biotech company to establish a wholly owned operation in the area. We have recently started construction of a hyaluronic acid (HA) facility which will be the world's first HA manufactured in an animal-free, solvent free environment. The facility will be run in full compliance to ICH/Q7 guidelines for API manufacturing and will represent a state of the art facility for HA cGMP production.
Quality and safety of Novozymes products is paramount and significant measures are taken to ensure that they are not compromised by manufacturing locations. Selection of the highest quality raw materials, equipment, and highly skilled, international personnel is also crucial to the success of the manufacturing facility no matter where the location.
On completion of the facility, the U.S. Food and Drug Administration (FDA), as well as other international regulatory agencies will audit prior to operation with customer audits also expected.
It is through regulatory compliance and manufacturing to the highest quality standards that ensures product safety, quality and consistency.