Last week’s round -up;
10-21 January 2022

published 24 Jan 2022

Ph. Eur. Supplement 10.8 Implementation – Notification for CEP holders

Supplement 10.8 of the Ph. Eur. is now available and CEP Holders are invited to update their applications according to the revised monographs that will be implemented on the 1st July 2022. 16 revised Ph. Eur. monographs are now available including texts for ‘Calcium gluconate for injection’ and ‘Cholecalciferol concentrate (powder form)’. The article linked below provides a full list of the revised monographs as well as instructions for CEP holders and a description of information that should be submitted to the EDQM depending on the classification of the updates made to the monograph.

Manufacturers object to provisions in FDA’s microbiological quality guidance

An industry trade group and several manufacturers are calling for revisions to the FDA’s draft guidance on microbiological quality considerations for non-sterile drugs (NSDs). The draft guidance was designed to help manufacturers control microbiological contamination of their NSDs and stems from the Agency’s concerns over a high number of adverse events and recalls associated with contaminated products, including Burkholderia cepacia complex (BCC) in non-sterile water-based drug products. According to one manufacturer, one of the main issues with the guidance is a recommendation for the periodical identification of microorganisms in manufacturing facilities, which would be a “significant new requirement” that is not necessary for NSDs and which would be unsustainable. Another stakeholder has said that the new provision calling for manufacturers to test potential objectionable organisms for each nonsterile product, is not practical. Another issue brought up by the industry is that the draft FDA guideline is not aligned with the ICH Q7 guideline on APIs as the former calls for microbiological testing of components such as APIs and excipients, while the Q7 guidance does not. Further comments from stakeholders may be found in the RAPS article below.

Revised ICH Q9 guideline to improve risk assessments

The ICH has issued a revised ICH Q9(R1) guideline that aims to address the shortcomings of the current guideline by providing “more scientific and robust applications of quality risk management principles” leading to “fewer quality defects and recalls” and reduced costs for the pharmaceutical industry.

The revised Q9 guideline is intended to address four shortcomings of the current version:

· High levels of subjectivity in risk assessments and in QRM outputs

· Failure to adequately manage supply chain and product availability risks

· Lack of understanding as to what constitutes formality in QRM work

· Lack of clarity on risk-based decision making The revision includes new text which acknowledges that some degree of subjectivity in QRM is unavoidable while offering methods to reduce or control subjectivity.

The document also includes a new section on formality in quality risk management and contains new text on the role of QRM in addressing product availability risks. The revised guideline is open for public consultation until the 15th March 2022.


Phthalates are commonly used as softeners to make plastics more flexible and durable. They can also be found in adhesives, sealants, paints, rubber materials, wires and cables, flooring, packaging, food contact materials, medical devices and sports equipment. Several ortho-phthalates may have endocrine effects and may affect the sexual development of boys which can lead to infertility in adults. Some phthalates are also harmful to the environment. From the 7th July 2020 the use of phthalates has been restricted in the EU/EEA. These restrictions are estimated to save approximately 2000 boys per year from impaired fertility. The Candidate List of substances of very high concern (SVHC) contains several ortho-phthalates. Manufacturers and importers must notify the ECHA if their products contain a substance on the list within six months after inclusion of the substance in the list. 14 phthalates are also on the REACH Authorisation List. Use of substances on the list will be prohibited after a given date unless the EC authorises the company to continue its use. Prior to applying for authorization, companies also need to demonstrate that the use of the substance is controlled, that there are no suitable alternatives and that the benefits of continued use exceed the risks.

FDA: Risk of benzene contamination in certain drugs

The FDA has alerted drug manufacturers to the risk of benzene contamination in certain drugs and is currently evaluating the root cause of contamination. Benzene is a known human carcinogen that causes leukaemia and other blood disorders. In pharmaceuticals, inactive ingredients such as carbomers (thickening agents), isobutane (a spray propellant), or other drug components made from hydrocarbons may be potential sources of benzene. The Agency is advising manufacturers to conduct risk assessments to evaluate the possible presence of benzene in their drug products and components, with a special focus on ingredients that are hydrocarbons or are manufactured with benzene or other hydrocarbons. According to ICH Q3C, benzene is classified as a Class I solvent and should not be used in the manufacture of drug substances, excipients, or drug products because of its unacceptable toxicity. However, the guidance does allow for limited cases where the presence of benzene may be tolerated up to a level of 2 ppm, unless otherwise justified. The article linked below provides information on how manufacturers should contact the FDA if benzene is detected in their drug products (including products that are already in distribution). It also contains information that the Agency may request during follow up.


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