FDA Archives - Real Regulatory

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An industry trade group and several manufacturers are calling for revisions to the FDA’s draft guidance on microbiological quality considerations for non-sterile drugs (NSDs). The draft guidance was designed to help manufacturers control microbiological contamination of their NSDs and stems from the Agency’s concerns over a high number of adverse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:

· 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

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.

Last week’s round -up;
03-07 January 2022

All you ever wanted to know about Ph. Eur. procedure 4 but never dared to ask

The EDQM has released a new document, ‘Procedure 4 (P4) – Everything you always wanted to know’, intended to help stakeholders understand the advantages of applying for monograph elaboration via this route. Procedure 4 monograph elaboration applies to active substances (and corresponding medicinal products) or excipients present in medicinal products that are still under patent or single source, provided that the medicinal product has been approved in at least one member state of the pharmacopoeial convention. It also applies to monographs on biotherapeutics as elaborated by the P4bio Working Party Advantages of P4 elaboration are: 1. Direct contact with the EDQM. 2. Regular updates during the elaboration process / full transparency. 3. Specifications as approved by the licensing authorities are unchanged. 4. A CEP can be requested immediately after adoption of the new monograph.

More clarity on ICH continuous manufacturing guideline requested

Several industry trade associations have requested more clarity on the ICH Q13 guideline on continuous manufacturing (CM), which covers CM of drug substances and drug products, including chemical entities and therapeutic proteins. Stakeholders have asked for clarity on what constitutes a state of control for a CM process, the scope of the guideline, and the definition of a batch size. More clarity on whether the principles in the guideline also apply to ATMPs has been requested. A stakeholder has also suggested that an example of a CM process being in a “state of control” should be provided as this would help in demonstrating when a state of control has been achieved. It has also been suggested that the definition of a batch should be expanded to include additional examples. Another stakeholder has suggested that the section of the guideline on non-conforming material or waste in CM should be revised, as manufacturing waste has not been a significant issue in CM. It has also been suggested that the guideline should make a clearer distinction between CM of small molecule drugs and biologics, since regulatory review, inspection, and management of post-launch process changes can differ significantly.

New FDA Guidance on the Inspection of Injectable Products for Visible Particulates

The FDA has released a new draft guidance on the Inspection of Injectable Products for Visible Particulates – Guidance for Industry. The draft guidance focusses on the development and implementation of a holistic, risk-based approach to visible particulate control that incorporates product development, manufacturing controls, visual inspection techniques, particulate identification, investigation, and corrective actions designed to assess, correct, and prevent the risk of visible particulate contamination. The guidance also clarifies that compliance with an applicable USP compendial standard alone is not generally sufficient for meeting the current GMP requirements for the manufacture of injectable products. However, the guidance does not cover subvisible particulates or physical defects that products are typically inspected for along with inspection for visible particulates such as container integrity flaws, fill volume, appearance of lyophilized cake/suspension solids.

Last weeks’ round -up;
15-26 November 2021

Good Machine Learning Practice (GMLP) – Guiding Principles

As the artificial intelligence and machine learning medical device field evolves, so too must best practice in Good Machine Learning Practice (GMLP). Through regulatory collaboration between the U.S. FDA, Health Canada, and the MHRA, 10 guiding principles have been identified which should be addressed when medical devices use artificial intelligence and machine learning software. These 10 guiding principles, which address the unique nature of these products are intended to lay the foundation for developing GMLP, in addition to the promotion of safe, effective, and high-quality medical devices that use artificial intelligence and machine learning.

Updated mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products

The FDA has received reports of certain types of nitrosamine impurities that formed in several drug products. These nitrosamines share structural similarities to the active ingredient and are therefore referred to as drug substance-related impurities (NDSRIs). NDSRIs may be generated during manufacturing or during the shelf-life storage period of the drug product. NDSRI formation has also been attributed to nitrite impurities present in commonly used excipients, including water, at parts-per-million amounts. Manufacturers are expected to use the three-step mitigation strategy described in the FDA’s guidance (Control of Nitrosamine Impurities in Human Drugs) to determine the presence of nitrosamines, including NDSRIs in their drug products. The Agency is encouraging applicants to develop control strategies and/or design approaches to reduce NDSRIs to acceptable levels if unacceptable levels are detected. One mitigation strategy described in the guidance includes a supplier qualification program for potential nitrite impurities across excipient suppliers and excipient lots to reduce the risk of nitrosamine formation in the drug product.Other possible mitigation strategies are also described in the FDA article linked below.

CMDh meeting: Ph. Eur. finished product monographs / EMA

The CMDh has published the minutes for the meeting held between the 12th and 14th October 2021. During the meeting the QWP responses to the CMDh questions on Ph. Eur. Medicinal Product Monographs (MPMs) were presented. The QWP has advised that, in principle, already authorised products for which a Ph. Eur. MPM is official should comply with the requirements described in the monograph, unless otherwise described in the General Notices of the Ph. Eur. If the MPM is official before a generic product is approved, the generic product has to comply with the requirements described in the monograph. However, if the generic product is approved before the MPM is developed, the MPM should have been developed to embrace the quality of all approved medicinal products. If this has not been the case and the generic product specification is wider than the range described in the MPM, this should be communicated to the National Pharmacopoeia Authority and EDQM to be considered for inclusion in a revised monograph. Several other scenarios are also described in Section 3.9 of the meeting minutes below.

Last weeks’ round -up;
01-12 November 2021

FDA releases 48 new and updated product-specific guidances

The FDA has released 48 new or updated product-specific guidances (PSG) as well as a newly developed infographic that provides a snapshot of the overall PSG program. The new draft PSGs include guidances to aid in the development of generics for the malaria treatment artesunate, the non-statin cholesterol lowering drug bempedoic acid, small cell lung cancer therapy lurbinectedin, the cholangiocarcinoma treatment pemigatinib, and migraine drug rimegepant sulfate, among other reference listed medicines. The FDA’s webpage on upcoming PSGs for complex generic drug product development has also been updated, with the agency’s progress in meeting its commitments under the reauthorization of the Generic Drug User Fee Amendments (GDUFA II).

PDG signs-off on milestone harmonised general chapter on chromatography

On the 28th September 2021, the Pharmacopoeial Discussion Group (PDG) signed off the harmonised general chapter on Chromatography, which brings together the Ph. Eur., JP and the USP texts. The chapter contains harmonised requirements which promote the development of individual monographs with a consistent approach and enhance understanding of basic requirements by users in all three regions. Particular attention was paid to:

· System suitability: this section provides requirements intended to guarantee that the performance of the chromatographic system is appropriate. They apply to multiple monographs and are to be read in conjunction with the requirements described therein.

MDCG issues new Q &A document regarding repackaging and relabelling of medical devices

MDCG 2021-26 Questions and Answers on repackaging & relabelling activities under Article 16 of Regulation (EU) 2017/745 and Regulation (EU) 2017/746

FDA: Nitrosamine detection tests should be ‘fit for purpose’

The US FDA has advised manufacturers that analytical tests used for the detection of nitrosamines should be “fit for purpose” in order to ensure that the right test is measuring the right impurity. The Agency has also advised that orthogonal (additional) methods should be used to double-check results. Nitrosamine contamination can be process-related, the impurities may be introduced via the supply chain or formed over the shelf-life of the drug product. The RAPS article below describes various case studies highlighting the importance of cross-checking and using analytical methods that are fit for purpose while conducting nitrosamine risk assessments.

Medical Device Coordination Group issues new guidance for legacy devices

MDCG 2021-25 Application of MDR requirements to “legacy devices” and to devices placed on the market prior to 26 May 2021 in accordance with Directives 90/385/EEC or 93/42/EEC

Revised ICH guideline on general considerations for clinical trials, ICH E8(R1)

The revised ICH guideline on general considerations for clinical trials [ICH E8(R1)] has been adopted by the Committee for Human Medicinal Products and will come into effect on 14th April 2022. This is the first time the guideline has been revised since its original adoption in 1997, and its update is being considered the “first step towards the Renovation of Good Clinical Practice initiated in 2017”. The revised guideline adopts quality-by-design principles and highlights fit-for-purpose data quality as one of the essential considerations for all clinical trials. Main updates identified from the previous version are a basic set of critical-to-quality factors that can be adapted to different trials, incorporation of a broader range of trial designs and data sources, and an updated cross-referencing of all other relevant ICH Guidelines that should be referred to when planning clinical studies.

Last week’s round -up;
04 -08 October 2021

EU extension of GMP and GDP certificates through 2022

EU regulators have automatically extended GMP and GDP certificates and other time-limited authorisations (manufacturing, import and wholesale authorisations) through 2022 due to COVID-19 safety and travel restrictions. This has been done to ensure the availability of medicines throughout the EU during the pandemic. For sites within the EEA, the extensions should occur without any action on the part of the certificate holder, unless any restrictions on the validity period are stated in the clarifying remarks of the certificate or the issuing/supervisory authority takes action that affects the validity of the certificate. The automatic extension does not apply to changes in the scope of the certificate. Distant assessments by an EEA supervisory authority may be required for new sites in third countries when no applicable mutual recognition agreement (MRA) exists with local regulators.

Risk of the presence of mutagenic azido impurities in losartan API

Following a report about the possible presence of potentially mutagenic azido impurities in certain sartan active substances, the EDQM has taken a number of measures to ensure that any active substances containing these impurities above the acceptable level would not be released onto the market. Holders of impacted CEPs were also requested to take corrective action to ensure that such impurities do not exceed their acceptable limits in the future. The EDQM’s recent investigations identified another azido impurity that has so far only been detected in losartan potassium (losartan azido impurity). This impurity has tested positive in a bacterial mutagenicity (Ames) test. The Directorate has advised that this azido impurity should be controlled at or below the Threshold of Toxicological Concern (ICH M7) due to the lack of additional information from in vivo studies. CEP holders were advised of their obligation to provide appropriate information relating to azido impurities to MAHs, therefore, enabling them to fulfil their legal responsibilities.

FDA: Microbial contamination in non-sterile drugs

The FDA has issued draft guidance to help manufacturers control microbiological contamination of non-sterile drugs (NSDs) due to concerns over a high number of adverse events and recalls associated with contaminated products. The draft guidance covers product development considerations, risk assessments, and GMP requirements that are relevant to control microbiological contamination in the manufacturing of a non-sterile drug. Solid non-sterile dosage forms as well as semi-solid forms and liquid non-sterile dosage forms including topically applied creams, lotions and swabs; and oral solutions and suspensions are covered in the guidance. The draft guidance applies to prescription or non-prescription drugs and approved NDAs or ANDAs as well as over-the-counter monograph drugs. Adverse events and recalls of drug products due to Burkholderia cepacia complex (BCC) contamination are included in the guidance, and prevention and testing for BCC in aqueous dosage forms of NSDs are also described. Further information on the draft guidance may be found in the link below and the deadline for comments is the 30th December.

Updated EMA Nitrosamines Q&A

A new draft Ph. Eur. monograph on Particle Size and Shape Determination by Image Analysis has been published in Pharmeuropa 33.4 for public consultation until the 31st December 2021. Image analysis is a computer-based technique used to determine the size and shape of particles from digital images efficiently and reliably. The images may be obtained by several techniques including optical microscopy, chemical imaging or electron microscopy. The measuring principle is based on a discretisation of an image into ‘pixels’, which are calibrated with respect to size and a software algorithm assigns the pixels to individual particles, which are thus characterised by a defined number of pixels of known size. The new guidance covers both static and dynamic image analysis. The dynamic technique can measure more particles than in static image analysis and is more reliable for wide size distributions, however, the technique is prone to systematic errors with respect to size.

Last week’s round -up;
13 -17 September 2021

New EMA Product-Specific Bioequivalence Guidance

The EMA has adopted the following new product-specific bioequivalence guidance, which come into effect on the 1st November 2021:

· Palbociclib hard capsule 75 mg, 100 mg and 125 mg and film-coated tablet 75 mg, 100 mg and 125 mg

FDA’s novel excipient pilot program opens for candidates

The FDA has launched a new pilot program to review novel excipients for use in meeting unmet needs in formulating new drug products. The Authority will accept four initial proposals in the pilot “but will consider accepting more proposals as resources allow.” The following criteria will be used to select candidates:

· The potential public health benefit of the novel excipients; for example, such applications as use in opioid abuse-deterrent formulations or to promote new therapies for serious and life-threatening disease.

· The likelihood of the novel excipient manufacturer’s ability to submit a complete package within the established timeframe.

· The potential of the novel excipient to “meaningfully improve pharmacokinetic characteristics” and lead to the development of novel drugs. Following acceptance of the initial proposals, the excipient manufacturers concerned will then be requested to submit a full toxicology package as well as chemistry, manufacturing, and controls data in a process parallel to that for an investigational new drug application. Proposals for novel excipients are being accepted until the 7th December 2021.

New Ph. Eur. general chapter on balances

The Ph. Eur. Commission has adopted a new general chapter Balances for analytical purposes (2.1.7), which has been published in Supplement 10.6 in July 2021. This new chapter fills a gap in section 2.1 Apparatus by setting out clear requirements for the use of analytical balances, as weighing is one of the most critical tasks carried out in the laboratory since even the smallest error will affect the accuracy of results. The chapter covers installation and use of analytical balances, including good practices for weighing vessels and provides detailed information on calibration and performance checks. These checks focus on two weighing parameters that most significantly affect balance performance, repeatability and sensitivity. The result of the repeatability test described in the text can also be used to calculate the minimum weight of the balance. The new chapter complements existing guidelines for the use and qualification of balances. It is supplemented by the instructions related to “Quantities” given in the recently revised General Notices chapter, which is due to be published in Supplement 10.7.

Last week’s round -up;
30 August – 03 September 2021

New and Revised FDA Product-Specific Guidance

The US FDA has issued 23 new and 16 revised draft product-specific guidances which are intended to facilitate generic drug development, especially for medicinal products for which there are no approved generics. The newly issued guidance documents involve some products used to treat HIV, chronic obstructive pulmonary disease (COPD) and Cushing’s disease. Some of the new guidances for complex products cover ipratropium bromide nasal spray, ipratropium bromide inhalation spray and olodaterol hydrochloride inhalation spray. The FDA has also issued product-specific guidance for Type 2 diabetes drug semaglutide, which offers two paths to establishing bioequivalence.

Herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids

The EMA has released a revised public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs). The document also includes recommendations regarding contamination of herbal medicinal products with PAs. Several PAs are regarded as both hepatotoxic and carcinogenic and are natural constituents of a number of plants used for medicinal purposes. This guidance describes chemical, toxicological, pharmacological and pharmacokinetic properties of PAs and sets out recommendations for the oral and cutaneous use of herbal medicinal products and traditional herbal medicinal products containing PAs. The revised public statement is a result of a review of newly available data and improved evaluation methods.

MHRA Guidance on Transfer of Analytical Methods

The MHRA Inspectorate has released new guidance for manufacturers and contract testing laboratories related to the process of transferring a method for outsourcing of testing. The Inspectorate has highlighted that the new guidance complements the requirements of EU GMP Chapter 7. The new guidance covers the formal process for the introduction of new methods which allows the receiving laboratory to demonstrate that they can perform the analytical method effectively and reproducibly. It also highlights that regulatory compliance is a shared responsibility between the transferring and receiving laboratories and a collaborative approach is encouraged. The MHRA has also recommended the use of risk management principles for analytical method transfer and the generation of a transfer report following a successful or even unsuccessful method transfer. A list of common shortcomings related to analytical method transfer is also included in the guidance.

Last week’s round -up;
23-27 August 2021

New multi-analyte methods for evaluating migration from printing inks

The EDQM has released an inter-laboratory study, conducted in 2020, on multi-analyte methods for the determination of substances migrating from printing inks to food or food simulants. The study is part of the process in the development of guidelines related to the quality and safety of materials and articles which come into contact with food. The new analytical methods were validated by 11 control laboratories and are intended for competent authority laboratories and for private laboratories to assess the safety of food contact materials and articles. These analytical procedures detect contaminants which can pass into food from printed packaging including 6 photoinitiators, 3 related degradation products and 1 plasticiser.

EMA Reflection Paper on Statistical Methodology for Comparative Assessment of Quality Attributes

The EMA has adopted a Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development. The reflection paper provides statistical methodology for the comparative assessment of quality attributes in the settings of pre- and post-manufacturing change, biosimilar development and generics development. The paper addresses questions related to comparison objectives, sampling strategies, sources of variability, acceptance ranges and statistical analysis approaches to conclude on the similarity of two drug products based on quality attribute data. The main objective of the guidance is to establish a framework and a common language to facilitate future discussion among stakeholders and to invite comments in relation to the issues raised. This guidance complements other available regulatory guidance on comparative data assessment of quality attributes, but it also contains more detail on how to carry out the comparison task based on empirical sample data.

FDA stands by nitrosamine risk assessment deadline

The US FDA has rejected the pharmaceutical industry’s request to extend the deadline for conducting nitrosamine risk assessments to 1st September from the original 31st March 2021 deadline. In September 2020, the FDA issued guidance on nitrosamine testing for pharmaceuticals, which required manufacturers to assess the nitrosamine impurity risks associated with all chemically synthesized APIs and all approved or marketed drug products that contain those APIs or other sources of nitrosamines by 1st March 2021. The FDA extended the deadline to 31st March due to complaints received from the industry. The industry then requested a further extension to 1st September due to the “time-consuming” and “resource-intensive” risk assessments required. The industry also expressed concern that the global supply chain may be affected due to the “magnitude of the risk assessments and subsequent confirmatory testing” resulting in drug shortages. Although the FDA has worked with manufacturers that have detected a high amount of nitrosamine contamination to mitigate drug shortages, the Administration has said that it has “not planned for additional extensions at the current time”.

SWP opinion on Diethanolamine and Coconut Oil Diethanolamine Condensate as excipients

The EMA has issued the opinion of the Safety Working Party (SWP) regarding diethanolamine and coconut oil diethanolamine condensate as excipients. There are carcinogenicity and genotoxicity concerns because diethanolamine has been shown to have carcinogenic potential in mice. The SWP’s conclusions regarding use of these excipients in medicinal products were: (1) MA holders should assess whether the use of the excipients in their products is still justified. PDEs of 53 micrograms/day and 705 micrograms/day were set for lifetime use and for use up to 12 months respectively. For the condensate, the level of contamination with diethanolamine should be identified and controlled at the PDE. (2) The possibility of formation of the nitrosamine impurity NDELA must be avoided. (3) For rinse-off medicinal products, retention factors of 0.01 and 0.1 are considered acceptable for diluted and undiluted products respectively.

Last week’s round -up;
16-20 August 2021

ATMPs containing genetically modified cells – draft EMA guidance on PI for consultation

The EMA has published for consultation a draft guideline detailing the information to be included in the Summary of Products Characteristics (SmPC), labelling and packaging leaflet for Advanced Therapy Medicinal Products (ATMPs) containing genetically modified cells. The purpose is to provide applicants and regulators with harmonised guidance on the requirements for the Product Information (PI); the consultation period ends on 31st October 2021.

The UK’s NICE has launched a consultation on Review of Methods and Processes for HTA Evaluation

NICE has just published a consultation on proposals for change as part of its methods and processes review. The consultation period is open for eight weeks. As newer more advanced technologies become available the outcome is intended to help simplify NICE’s approach and to allow more flexible decision-making. All while continuing to be robust and responsive.

Full details of the consultation and a short video outlining the proposed changes, can be found here: https://lnkd.in/ecXED6rE

New ICH Q13 continuous manufacturing guideline

The ICH has released a new draft ICH Q13 guideline on continuous manufacturing of drug substances and drug products, which is open for public consultation in Europe until the 20th December 2021. The new guideline covers continuous manufacturing (CM) of drug substances and drug products for both chemical entities and therapeutic proteins and may also apply to other biological/ biotechnological entities. It provides guidance on CM for new products, including generics and biosimilars, and also on the conversion of batch manufacturing to CM for products that are already on the market. The guidance focuses on the integrated aspects of a CM system in which two or more unit operations are directly connected, therefore, any changes made in a unit operation of CM may have a direct and often immediate impact on downstream and upstream unit operations. The main body of the guideline covers fundamental aspects of CM that are not specific to technology, dosage form, or molecule type. The annexes contain illustrative examples and considerations specific to certain modalities (e.g. chemical entities, therapeutic proteins), technologies, and production methods (e.g. integration of drug substance and drug product manufacturing).

Update on replacement for EMA electronic application forms (eAFs)

Further details have been released for the Digital Application Dataset Integration (DADI) project to replace the current pdf-based human and veterinary medicine eAFs, from 2022 onwards, with web-based forms on a portal. A summary presentation of the project, an updated questions and answers document, and a features list for the human variations form, are available on the eSubmission website.

Clarity sought from the US FDA on ICH Q12 implementation

Following a public consultation, the US FDA has received several comments on its draft guidance on how ICH Q12 is to be implemented in the US. The ICH Q12 guideline facilitates the management of postapproval CMC changes for new and marketed pharmaceuticals and drug substances. Some members of pharmaceutical industry have asked the FDA to align reporting categories with the ICH Q12 guideline on postapproval changes. Other members seek clarity on how manufacturers can use postapproval change management protocols (PACMPs) to support a lower reporting category. Clarity has also been requested on whether the new guidance replaces the Agency’s guidance on established conditions (ECs) that was published in 2015 or whether the two guidelines should be used in conjunction.

Last week’s round -up;
19-23 July 2021

New Ph. Eur. Golimumab concentrated solution monograph

The EDQM has released a new draft monograph on a single-source anti-TNF-alpha monoclonal antibody, Golimumab concentrated solution. The Ph. Eur. Commision has used the single-source approach to elaborate this draft monograph and the text reflects the considerations outlined in the EDQM’s scientific publication on “Elaborating European Pharmacopoeia monographs for biotherapeutic proteins using substances from a single source”. The draft monograph is open for public consultation until the 30th September 2021.

Notification for CEP holders: Implementation of Ph. Eur. Supplement 10.6

Ph. Eur. Supplement 10.6 is now available and the EDQM has invited CEP holders to update their applications according to the revised monographs that will be implemented on the 1st January 2022. The Directorate has provided a list of substances covered by a CEP and for which a revised monograph will be implemented, and updates are classified into two categories, “Case A” and “Case B”. “Case A” concerns cases where the specification of the substance should be updated according to the revised monograph. “Case B” concerns amendments to the monograph which require the submission of data to the EDQM. In the article linked below, the EDQM has provided detailed instructions for CEP holders and manufacturers on how to proceed depending on which case the updates relate to.

FDA ICH Q12 EC Pilot Program

ICH Q12 facilitates the management of post-approval CMC changes for new and marketed drug products and drug substances. According to the guideline, regulators will allow manufacturers to identify and submit established conditions (ECs) for new drug applications and prior approval supplements. ECs are defined as “legally binding information considered necessary to assure product quality.” Manufacturers can propose reporting categories for post-approval changes after identification of ECs. In 2019, the US FDA started the EC Pilot Program where sponsors could propose explicit established conditions (ECs) as part of an original new drug application, abbreviated new drug application, biologics license application or as a prior approval supplement.

The following RAPS article outlines the outcome of the pilot program and discusses the different approaches taken by manufacturers when defining ECs:https://bit.ly/RealCMC-3zfE60L

Revised Ph. Eur. general chapter on chemometric methods applied to analytical data

The revised general chapter Chemometric Methods Applied to Analytical Data (5.21) has been published in Pharmeuropa 33.3 and is open for comments until the 30th September 2021. This general chapter is published for information and is an introduction to the use of chemometrics and data science techniques. Some of the updates in the revised Chapter include: · An update of section 1 ‘General aspects’ with a review of parts of ‘Pre-processing’ and ‘Assessment and validation of chemometric methods’. · Two new sub-sections on ‘Independent component analysis’ and ‘Decision trees and random forests’. · A general review of sub-sections on ‘Similarity measures’, ‘Clustering’, ‘Multiple linear regression’, ‘Principal component regression’, ‘Support vector machines for supervised classification’ and ‘Artificial neural networks’. · A new section, 3. ‘Related application fields’, including sub-sections on ‘Chemometrics in chemical imaging’ and ‘Data fusion’. · An update of the Glossary and the Abbreviations.

Real Regulatory is now part of tranScrip – your life science powerhouse.

In March 2022, Real Regulatory became a subsidiary of tranScrip, a leading contract drug development organisation supporting the entire life cycle of medicines.

As a result, this website is now closed. You can now keep up-to-date with us at www.transcrip-group.com

This is a really exciting journey for both companies and we look forward to working with you on your development programmes, from discovery through to post-licensing.

Thank you.

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

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

Manufacturers object to provisions in FDA’s microbiological quality guidance

Revised ICH Q9 guideline to improve risk assessments

Phthalates

FDA: Risk of benzene contamination in certain drugs

Last week’s round -up; 03-07 January 2022

All you ever wanted to know about Ph. Eur. procedure 4 but never dared to ask

More clarity on ICH continuous manufacturing guideline requested

New FDA Guidance on the Inspection of Injectable Products for Visible Particulates

Last weeks’ round -up; 15-26 November 2021

Good Machine Learning Practice (GMLP) – Guiding Principles

Updated mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products

CMDh meeting: Ph. Eur. finished product monographs / EMA

Last weeks’ round -up; 01-12 November 2021

FDA releases 48 new and updated product-specific guidances

PDG signs-off on milestone harmonised general chapter on chromatography

MDCG issues new Q &A document regarding repackaging and relabelling of medical devices

FDA: Nitrosamine detection tests should be ‘fit for purpose’

Medical Device Coordination Group issues new guidance for legacy devices

Revised ICH guideline on general considerations for clinical trials, ICH E8(R1)

Last week’s round -up; 04 -08 October 2021

EU extension of GMP and GDP certificates through 2022

Risk of the presence of mutagenic azido impurities in losartan API

FDA: Microbial contamination in non-sterile drugs

Updated EMA Nitrosamines Q&A

Last week’s round -up; 13 -17 September 2021

New EMA Product-Specific Bioequivalence Guidance

FDA’s novel excipient pilot program opens for candidates

New Ph. Eur. general chapter on balances

Last week’s round -up; 30 August – 03 September 2021

New and Revised FDA Product-Specific Guidance

Herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids

MHRA Guidance on Transfer of Analytical Methods

Last week’s round -up; 23-27 August 2021

New multi-analyte methods for evaluating migration from printing inks

EMA Reflection Paper on Statistical Methodology for Comparative Assessment of Quality Attributes

FDA stands by nitrosamine risk assessment deadline

SWP opinion on Diethanolamine and Coconut Oil Diethanolamine Condensate as excipients

Last week’s round -up; 16-20 August 2021

ATMPs containing genetically modified cells – draft EMA guidance on PI for consultation

The UK’s NICE has launched a consultation on Review of Methods and Processes for HTA Evaluation

New ICH Q13 continuous manufacturing guideline

Update on replacement for EMA electronic application forms (eAFs)

Clarity sought from the US FDA on ICH Q12 implementation

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New Ph. Eur. Golimumab concentrated solution monograph

Notification for CEP holders: Implementation of Ph. Eur. Supplement 10.6

FDA ICH Q12 EC Pilot Program

Revised Ph. Eur. general chapter on chemometric methods applied to analytical data

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