Last week’s round-up, 02-06 December 2019

By Stephanie Allampalli and Marthese Mifsud


Metformin is being evaluated for nitrosamine impurity content.

06 December 2019

The Singaporean Health Sciences Authority has recalled some metformin products due to unacceptable levels of NDMA.

On 5th December, the US FDA issued a statement saying that it has started evaluating metformin products for nitrosamines. (See link to FDA statement :

At the time of writing, EMA has not issued a public statement yet, but an emailed EMA statement has been quoted in various articles: “Authorities in the EU are asking companies to investigate and to test metformin medicines in the EU for NDMA and to report back with the results”.


Link to article :

EC Considers Amending Provision on Duplicate MAAs for Biologics

06 December 2019

The European Commission (EC) is considering amending the provision on duplicate marketing authorization applications (MAAs) for biologics, including duplicate reference biologics, also known as “autobiologicals”. Biosimilar manufacturers obtain duplicate MAAs in order to increase the availability of their products in certain markets.

However, there is concern amongst national competent authorities (NCAs) and the generic and biosimilar industries, as autobiologicals can be considered generics. This poses a problem in markets where pharmacy substitution for biosimilars is not allowed. There is also concern that autobiologicals may allow originator companies “to severely undercut the price of potential biosimilar competitors while allowing the reference originator product to maintain a high price”.

The EC has proposed that any requests for duplicate MAs need to be properly substantiated and based on sound evidence. Most member state NCAs have requested further clarity on the proposal and have recognized that autobiologicals “have a potential to adversely affect availability in the long run”.

Overcoming Bioavailability ‘Roadblocks’ with LBDDS

04 December 2019

Lipid-based drug delivery systems (LBDDS) have gained importance in the pharmaceutical industry due to their ability to increase the bioavailability of drug products. Over 70% of new chemical entity (NCE) molecules are poorly soluble, therefore, LBDDS play an important role in the formulation of NCEs.

Lipid-based formulations increase bioavailability by providing excellent solubilization capacity, improving permeation, overcoming transporter and enzyme-based inhibitions and by supporting lymphatic transport. By increasing the solubility of APIs, lipid-based formulations also improve dose-uniformity, thus, reducing patient-to-patient variability. Lipid-based formulations are versatile and can be administered via different routes including oral, injectable and topical.

However, several challenges may also be encountered in the use of LBDDS, such as issues with stability of the formulation and low drug loading. Research is underway to overcome these challenges and increase the use of lipid-based excipients in the formulation of poorly soluble NCEs.

FDA Drafts Guidance on Transdermal and Topical Drug Delivery Systems

03 December 2019

The FDA has issued a draft guideline for transdermal and topical delivery systems (TDS) for new and generic drugs, which focusses on product development, manufacturing and quality. The document also covers other issues that may affect the performance of drugs delivered through a TDS, such as adhesion failure and applied heat. The guideline also indicates the information to be submitted in applications for medicines delivered via TDS.

According to the FDA, most transdermal and topical delivery systems can be categorized as either matrix type and liquid or gel reservoir type, and that both systems “present similar manufacturing and quality control concerns”. The new guidance may not apply to other types of TDS such as microneedles, active transport TDS or TDS applied to broken skin. Applicants are advised to focus on matrix type TDS due to “inherent failure modes and safety risks associated with reservoir TDS”.

Risk-Based Intermediate Precision Studies for Analytical Procedure Validation

02 December 2019

In order to validate analytical procedures, a study of intermediate precision for within-laboratories variations is required. However, there is a lack of global guidance with regards to the design of intermediate precision studies.

Intermediate precision studies can be designed by applying science-based and risk-based principles, aligned with quality by design (QbD), thus ensuring that the factors chosen reflect the highest risk of impacting the performance of the analytical procedure. Also, the overall risk/complexity of the procedure should be associated with the number of independent analytical runs carried out in the procedure.

The Japanese National Institute of Health Sciences (NIHS) has provided useful pre-QbD guidance which proposes a generic design that utilizes six independent analytical runs. Several examples of intermediate precision studies illustrating the proposed NIHS design are described, including a reversed-phase HPLC assay method to quantify a process-related solvent in an API, a cascade impaction method for an inhaled device and an automated content method for a tablet.

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