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# Latest news on …

GAYLE DE MARIA
Chimica Oggi – Chemistry Today (TKS Publisher)

IPEC Europe Task Force acts to help industry meet EU risk assessment guidelines for Excipients

IPEC Europe's recently-formed Risk Assessment Task Force is preparing a document to help pharmaceutical manufacturers comply with the EU Guidelines on risk assessment for excipients (2015/C 95/02). At its inaugural face-to-face meeting on 1 July in Brussels, the Task Force agreed that a 'how-to' document will help drugmakers establish the appropriate GMP for excipients used in their products. The need is urgent as risk assessments for all excipients must be completed before the deadline of 21 March, 2016. The compliance guide will draw on the experiences of both excipient suppliers and pharmaceutical manufacturers, according to the Task Force. It will cover the scope of the guideline, emphasise the new requirements that will come into play and detail the responsibilities of excipient manufacturers, distributors and users. The document will also identify risk-mitigation activities and provide advice on how to resolve any conflicts that may emerge during the process, amongst other aspects. Practical examples will be included. In May, the IPEC Federation* published a position statement noting that considerable effort will be required by the industry in order to complete all excipients risk assessments by the deadline. "The implementation of appropriate excipient GMPs by suppliers will require more than a year, and may be difficult to achieve for manufacturers of certain substances not typically produced as pharmaceutical excipients," says the statement. "Incomplete assessments may jeopardize the availability of high quality excipients that have been in use for many years." Stakeholders who would be interested in taking part in the preparation of the new compliance guide - which is scheduled for publication in October - are invited to contact the IPEC Europe Secretariat. The IPEC Europe Risk Assessment Task Force includes representation from leading suppliers and users of pharmaceutical excipients.

* The IPEC Federation represents the four existing regional International Pharmaceutical Excipient Councils: IPEC-Americas, IPEC Europe, IPEC Japan and IPEC China.

IPEC Europe Secretariat: info@ipec@europe.org

IPEC-Americas presents novel excipients review rationale at FDA PDUFA meeting

On July 15, 2015, FDA held a public meeting to seek input on the reauthorization of the Prescription Drug User Fee Act (2002) (PDUFA). IPEC-Americas representative, David R. Schoneker, Director, Global Regulatory Affairs, Colorcon, IPEC-Americas Past Chairman and current Vice-Chair for User and Maker Relations, presented comments during the meeting. This presentation and comments centered on review and qualification of novel excipients. IPEC-Americas followed up on August 14, 2015 with a submission to the FDA docket on PDUFA Re-authorization with detailed written comments that describe the need for an independent FDA safety review/qualification process for novel excipients outside of the normal drug approval process. The key points included in the IPEC-Americas comments are summarized below.

The FDA defines new or novel excipients in their Guidance on Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients and this definition includes the following types of Novel excipients:

• New Co-Processed Excipients made from two or more previously approved excipients (usually manufactured using a physical process such as spray drying or melt extrusion)
• New uses of an Existing Excipient – examples would be:

- Higher level of use in a previously used route of administration

- Use in a new route of administration

• New Chemically Modified Grades of an Existing Excipient (minor changes to existing excipient)
• New Chemical Entity Excipients (NCEs) – these tend to be what people think of when discussing novel excipients. However the other types mentioned above are also considered to be novel excipients from a regulatory perspective.

The degree of newness for different types of novel excipients will influence the amount of safety data required to complete an appropriate assessment.

Novel excipients may be one important key to drug product improvements. They may address the following issues:

• patient compliance – through, for example, advancement of formulation of more patient friendly dosage forms
• development of high-quality drug products – through, for example, modification of drug plasma profiles
• advancement of manufacturing science for drug products – through, for example, enabling or facilitation of continuous manufacturing or other advanced manufacturing methods for drug products

Currently neither pharmaceutical companies (as excipient users) nor excipient manufacturers have incentives to use or develop novel excipients which can produce all three potential improvements discussed above.

Pharmaceutical companies are generally unwilling to risk the use of novel excipients because of the regulatory uncertainty of the current process to get them approved in their formulation which can result in delays in approval of their application. Novel excipients could be an important factor in controlling costs of drug development since formulators might then be able to use the “best tool (excipient) for the job” instead of having to formulate around an approved but sub-optimal excipient. In some cases, certain drug products may not be able to be developed using traditional excipients and novel excipients may be needed to resolve various physical issues with APIs such as poor solubility and permeability.

In the case of excipient manufacturers, it follows that if their customers are unwilling to risk using novel excipients, there is little incentive to develop them. This can, and in some cases does result in stagnating market growth and innovation.

In the current state of affairs, there is no mechanism for evaluation of excipients alone – they are only evaluated as part of drug products in NDAs and ANDAs.

This result sometimes leads to drug products which are “good enough” but which may not be optimal.

IPEC-Americas has proposed to FDA that it adopt a new regulatory review or qualification process for novel excipients which provides for stand-alone (independent) review and qualification of excipients by the agency. The intent would be for this new regulatory review or qualification to help mitigate the uncertainty associated with novel excipient use.

It is important to note that IPEC-Americas has not suggested that novel excipients would or should be “approved” outside of the drug approval process, but rather that there could be preliminary safety and qualification assessments independent of the drug but based on safety data that exists to support the intended route(s) of administration and intended use level(s).

Currently the only mechanisms that exist for excipient manufacturers to present excipient specific information to the agency independent of a drug application are Type IV (Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation) or Type V (FDA Accepted Reference Information) drug master files (DMFs). However, DMFs are only intended to be reviewed by the agency in conjunction with a specific drug application and there is no consistent approach to DMF reviews. This may result in refuse to receive notifications (for novel excipients that are not really new chemical entities) or application delays.

FDA toxicologists have referred IPEC-Americas to the Biomarker Qualification Program (BQP) as a possible model process for new excipients. IPEC-Americas believes that there are many important, relevant concepts in the program that, with modification, could provide a foundation for engaging FDA on modernizing a process for novel excipient safety review.

IPEC-Americas has offered to collaborate with FDA to define what the Agency would need to review in such a process. Information required for an excipient review could be similar to the type of information currently required for a Type II DMF for Active Pharmaceutical Ingredient (API) completeness assessment but with added focus on excipient safety.

There would also need to be development and implementation of a unique type of user fee system (different from the existing PDUFA user fee model) to fund FDA resources to perform independent safety assessments / qualifications of excipients.

IPEC-Americas has invited the FDA to continue discussions on possible approaches to create an improved pathway for review and acceptance of novel excipients based on defined criteria and mechanisms by which such a process could be formally recognized.

IPEC Americas: IPECAMER@ipecamericas.org

China's excipients market set to double between 2013 and 2017

The market for pharmaceutical excipients in China will grow from a value of 26.36 billion yuan (around $4bn) in 2013 to 54.83 billion yuan in 2017, according to market research figures. The report by Research in China notes that there are more than 500 types of pharmaceutical excipient in China, far less than 1,500 types found in the US and 3,000 types in Europe. By market size, gelatin capsules, sucrose, starch, film-coated powder, 1,2-propylene glycol, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), microcrystalline cellulose, hydroxypropyl cellulose (HPC) and lactose rank as the top 10 pharmaceutical excipients in China. In the first half of 2014, China's gelatin capsule export volume amounted to 1,427.5 tons and the export value reached$32 million, according to the report. However, China still relies on the import of film-coated powder, PVP and other new-type high-end pharmaceutical excipients.

Currently, pharmaceutical excipients account for about 2 to 3 per cent of China's total output value of pharmaceutical preparations. There are about 400 pharmaceutical excipient manufacturers in China, of which more than 90 specialize in the production of pharmaceutical excipients, with the remainder focusing on chemical or food processing.

IPEC Europe

Sanofi and MannKind announce Afrezza®, the only inhaled insulin, now available in the U.S.

Sanofi and MannKind Corporation announced beginning of 2015 that Afrezza® (insulin human) Inhalation Powder, the only inhaled insulin, is now available by prescription in U.S. retail pharmacies nationwide. Afrezza is approved by the U.S. Food and Drug Administration to control high blood sugar in adults with type 1 and type 2 diabetes.

“Many people living with diabetes are not able to control their blood sugar on their current medications and may benefit from using insulin. Now they have another option to administer insulin that is not an injection,” said Dr. Janet McGill, M.D., Professor of Medicine at Washington University School of Medicine in St. Louis and Afrezza clinical trial investigator. “This delivery option may help change the dialogue between health care professionals and people living with diabetes about initiating or intensifying insulin therapy.”

Afrezza is a drug-device combination product that consists of a dry formulation of human insulin delivered from a small and portable inhaler to help patients achieve blood sugar control. Afrezza is rapidly absorbed and has a short duration of action. It is administered at the beginning of a meal.

Afrezza can help control high blood sugar as part of a diabetes management plan that may include diet, exercise and other diabetes medications. Afrezza should not be used in patients with chronic lung disease such as asthma or COPD. Afrezza cannot be used to treat diabetic ketoacidosis. Afrezza is not recommended in patients who smoke or who have recently stopped smoking.

“Afrezza is an important addition to Sanofi’s growing diabetes portfolio of integrated, personalized offerings, and it is one that highlights our dedication to bringing innovative therapies to people with this disease,” said Pierre Chancel, Senior Vice President Diabetes Division, Sanofi. “There is a recognized need for an insulin that doesn’t require an injection, and our organization is committed to making this new treatment option available to patients.”

“We are extremely proud to see the many years of work that went into developing Afrezza culminate in the day when it is now available to help people manage their diabetes,” stated Alfred Mann, Executive Chairman, MannKind Corporation.

Afrezza is a rapid-acting, inhaled insulin used to control high blood sugar in adults with type 1 and type 2 diabetes. The product consists of a dry formulation of human insulin delivered from a small and portable inhaler. Administered at the beginning of a meal, Afrezza dissolves rapidly upon inhalation to the lung and delivers insulin quickly to the bloodstream. Peak insulin levels are achieved within 12–15 minutes of administration. Afrezza is available in 4-unit and 8-unit single-dose cartridges of insulin powder that can be used, as prescribed by a health care professional, in combination with other diabetes medications to achieve target blood sugar levels. For Afrezza doses exceeding 8 units, patients may use a combination of 4 unit and 8 unit cartridges. Other sizes of cartridges are being considered. The disposable inhaler can be used for up to 15 days, should be kept in a clean, dry place with the mouthpiece cover on and may be wiped with a clean, dry cloth if needed.

Sanofi and MannKind have entered into a worldwide exclusive licensing agreement to develop and commercialize Afrezza. Under the collaboration agreement, Sanofi is responsible for global commercial, regulatory and development activities.

Improved chitosan excipient - from a dung beetle

Chitosan is widely-used as an ingredient in dietary supplement but also has potential as an excipient in controlled-release formulations.

At present chitosan is extracted from the exoskeletons of shrimp and crab, but this means that supplies are seasonal, can potentially cause allergic reactions and -thanks to marine pollution - may pose other health risks.

Now, scientists in China say they have prepared chitosan from Catharsius molossus L - an abundant species of dung beetle belonging to the Scarabaeidae family that is encountered throughout tropical Asian regions and is used in traditional Chinese medicine.

They ran a battery of tests comparing the new chitosan with commercial medical-grade chitosan from shrimp and concluded it was superior "in the aspects of degree of deacetylation, crystallinity, heavy metal content, viscosity, protein residue, ash content, and in vitro adhesion."

One of the most interesting uses of chitosan as an excipient is in formulations that adhere to the colon and deliver their payload, avoiding first-pass metabolism.

Reference

Jiahua Maa et al., Journal of Biological Macromolecules, 80, 547–556, (2015)

Waste olive leaves could be source of excipients

Olive leaves pruned from trees used in agriculture could be a rich source of bioactive compounds, including pharmaceutical excipients, according to Spanish researchers.

At the moment olive leaves are typically burned or ground up and scattered - causing economic and environmental problems - but could instead be used as a valuable by-product, they note.

Alongside a number of phenolic derivatives, pentacyclic triterpenes and other compounds with potential pharmacological applications, olive leaves are also a rich source the naturally-occurring polyol mannitol, which is commonly used as a pharmaceutical excipient in the formulation of chewable tablets and granulated powders.

Mannitol is currently produced commercially by chemical hydrogenation of sugars. As mannitol is found in a significant amount in the olive leaves, "its production from this natural source can be considered as an interesting alternative," say the researchers.

Reference

Ángeles Guinda et al., LWT - Food Science and Technology, 64 (1), 431–438 (2015)