Real Regulatory continues to be certified to ISO9001:2015 standards

Delighted to share an update on our ISO 9001:2015 certification which we continue to successfully maintain.

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

https://bit.ly/RealCMC-3tK6ad0

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An industry trade group and several manufacturers are calling for revisions to the FDA’s draft guidance on microbiological quality considerations for non-sterile drugs (NSDs). The draft guidance was designed to help manufacturers control microbiological contamination of their NSDs and stems from the Agency’s concerns over a high number of adverse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

https://bit.ly/RealCMC-3txYMl3

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.

https://bit.ly/RealCMC-34Ncoym

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.

https://bit.ly/RealCMC-3A0iOFP

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.

https://bit.ly/RealCMC-3K8p435

 

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Last week’s round -up;
25-29 October 2021

Antimicrobial Resistance – expected regulatory implications

Activities of the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR) are expected to have regulatory implications. Mentioned within their current progress report are agreements on clinical trial recommendations that will be reflected in updated guidance documents for several different types of bacterial diseases. Also identified for continued collaboration up till 2026 are strategies to improve financial incentives, access, research, and development of antimicrobial drugs, diagnostics, and alternatives. Furthermore, the definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pan-drug-resistant (PDR) bacteria for human infections will be revised.

https://lnkd.in/euK-FM_f

Japan’s PMDA posts English translation of guidelines for bioequivalence studies

Japan’s PMDA has released an English translation of guidelines and questions and answers on bioequivalence studies of generic products.The guidelines cover bioequivalence studies, dissolution tests and other assessments for various dosage forms, including oral immediate release and oral extended-release products. The guideline also features a shorter section on non-oral dosage forms and dosage forms for which bioequivalence studies are waived.

https://bit.ly/RealCMC-3EsokCu

Guidance on good lay summary practice

Guidance on good lay summary practice (GLSP) has recently been published by the European Commission. The guidance provides recommendations on how to prepare, write, translate, and disseminate summaries of clinical trial results in lay language, and was adopted by the expert group on clinical trials in July 2021. Sponsors should note that lay summaries on each clinical trial are a mandatory requirement of the upcoming Clinical Trial Regulation. Relatedly, the guidance highlights mandatory requirements under the regulation, and those which are optional recommendations based on ethical obligations and related best practices.

https://lnkd.in/dzJMMANW

Updates from the EDQM

The EDQM has released the following updates:

• A revised osmolality chapter for public comment in Pharmeuropa. The revised chapter focuses on osmolality reference solutions using sodium chloride that are required for instrument verification. The deadline for comments is the 31st December 2021.

• The Pharmacopoeial Discussion Group is preparing a pilot for global expansion of membership to integrate additional world pharmacopoeias.

• CEP holders are invited to comment on draft monographs published in Pharmeuropa 33.4. The deadline for comments is 31st December 2021.

• CEP holders are invited to update their applications according to the revised monographs published in Ph. Eur. Supplement 10.7 that will be implemented on the 1st April 2022.

https://bit.ly/RealCMC-3nTq1lN

Public consultation on EU pharmaceutical legislation

The European Commission has launched a public consultation on the revision of the EU’s pharmaceutical legislation. The consultation will last until 21st December 2021 and will gather views from stakeholders and the general public. The last review of the EU’s pharmaceutical legislation took place almost 20 years ago and the overarching aims of this revision are: to ensure access to affordable medicines, foster innovation, improve security of supply, adapt to new scientific and technological developments, and reduce red tape. In the consultation, the EC also asks if there are other problems it needs to address.

https://lnkd.in/d6snDbtU

The EMA’s tailored scientific advice offering for biosimilar development will be continued

In its report on the initial pilot offering of tailored scientific advice for new biosimilar development, the EMA has announced that this will be continued as part of regular scientific advice operations. When using the procedure, developers are advised on the studies they should conduct, based on a review of the quality, analytical and functional data they already have available. The service will be capped at a maximum of 2 procedures per month, and the duration is set to 70 days if managed without a discussion meeting or 100 days if such a meeting is needed.

https://lnkd.in/eW6FtBem

Updated Q&A on GMP compliance for IMPs

The European Commission has released an updated Q&A no. 8.4 on the Clinical Trials Regulation 536/2014. The updated Q&A covers the documentation that is required to show compliance of an IMP and AxMP with GMP, which is also outlined in Chapter IX and Annex 1 section F of the CTR:

• No documentation is required for IMPs authorised in the EU (even if not manufactured in the EU).

• For IMPs that are not authorised in the EU and do not have an MA from a third country that is party to ICH, and are not manufactured in the EU, an authorisation referred to in article 61(1) and a QP declaration of GMP equivalence is required. In the latter case, if a Mutual Recognition Agreement (MRA) covering clinical trials is in place with the particular country, the latter declaration is not required if the MRA provides for GMP equivalence already.

• An authorisation according to article 61 of the Clinical trial Regulation is required for all other cases.

• Information regarding the GMP compliance of APIs is not required by the CTR (and can therefore not be required by the Member States concerned).

 https://bit.ly/RealCMC-3GpA3n5

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Last week’s round -up;
26-30 July 2021

EMA issues new draft guidance on core SmPC, labelling and package leaflet for ATMPS

EMA has opened up a consultation from 30th July 2021 through to 31st of Oct 2021 on a new guidance for ATMPS containing genetically modified cells. The guideline seeks to describe the information to be included in the summary of products characteristics (SmPC), labelling and package leaflet and it is intended to apply to allogeneic or autologous, including viral vector modified and genome edited cells. Examples for Chimeric Antigen Receptor T (CAR-T) cells and Cluster of Differentiation 34+ (CD34+) modified cells are given in more detail. These can be used as model wording for other types of genetically modified cells.

The draft guidance can be found here: https://lnkd.in/e8rPmDr

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. The new draft ICH Q13 consists of a main guideline and five annexes. The main guideline covers three different models of continuous manufacturing, and reviews control strategy and regulatory considerations. The three models of continuous manufacturing covered by the guideline include: 1. A combination of approaches in which some unit operations operate in a batch mode while others operate in a continuous mode 2. A model where all unit operations of a drug substance or drug product manufacturing processes are integrated and operate in a continuous mode 3. An approach in which the drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single continuous manufacturing process. The annexes cover continuous manufacturing of drug substances, as well as continuous manufacturing of drug products, therapeutic protein drug substances, integrated drug substances and drug products and perspectives for managing disturbances.

https://bit.ly/RealCMC-3rGnsoB

Attention CEP Holders: New Draft Ph. Eur. Monographs

The following fifteen draft Ph. Eur. monographs, for which CEPs have been granted, have been published in Pharmeuropa 33.3:

• Amylmetacresol

• Calcium acetate

• Calcium ascorbate

• Cholecalciferol

• Clodronate disodium tetrahydrate

• Diclazuril for veterinary use

• Estriol

• Isoniazid

• Ondansetron hydrochloride dihydrate

• Pemetrexed disodium heptahydrate

• Propylthiouracil

• Raltegravir potassium

• RRR-alpha-Tocopheryl acetate

• Thiamine nitrate

• Tibolone

The EDQM has therefore asked CEP holders to consult the list of substances and provide feedback on the draft monographs before the 30th September 2021.

https://bit.ly/RealCMC-3iaoC8z

EMA issues new guidance on quality documentation required for medicinal products when used with a medical device

The EMA has finally issued new guidance that focuses on product-specific quality aspects of a medical device, or device part, that may have an impact on the quality, safety and/or efficacy (and hence overall benefit/risk determination) of a medicinal product.

The guidance covers; Medicinal products where the medical device and/or device part form an integral product that is not reusable; Medicinal products that are co-packaged with a device;  Medicinal products that are required to be used with a specific medical device.

The guidance which is effective from 1st Jan2022, can be found here :

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-documentation-medicinal-products-when-used-medical-device-first-version_en.pdf

EMA has updated pre-authorisation guidance for users of the centralised procedure

By the end of September 2021 any new sites and organisations to be registered for a Medicinal Product Marketing Authorisation will have to have to be registered in the EMA’s Organisation Management Service (OMS). This will be mandatory and EMA is keen to stress the importance of this site registration before the regulatory submission in order to avoid any delay in the start of the MAA process. If not applicants will be requested to register the site(s)/organisations during validation and prior to the start of the procedure. The guidance now also give detail instructions on the withdrawal of a request for submission of an MAA to EMA, if the applicant no longer wishes to submit an MAA.

The latest document with full details of the pre-submission guidance from EMA can be found here: https://lnkd.in/g5YcXxj

Upcoming ICH Analytical Guidelines

The ICH intends to release two new guidelines, ICH Q14 and ICH Q2(R2), which should allow manufacturers to switch analytical methods for testing medicines post-approval more easily and allow for better lifecycle management. The upcoming ICH Q14 guideline will harmonize scientific approaches to analytical procedure development to allow for a more efficient, sound scientific and risk-based approval. The ICH Q2(R2) guideline will replace the current ICH Q2(R1) guideline and will include some of the newer analytical procedures. Together the two forthcoming ICH guidelines should create a harmonized performance-based approach for allowing analytical method changes. The new ICH guidelines should be available for public consultation in December 2021.

https://bit.ly/RealCMC-3y8O3wU

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Real Regulatory Ltd – NSAI I.S. EN ISO 9001:2015 Certified for another 3 years

We are proud to announce our successful re-certification to ISO 9001:2015 Standards following our two day re-assessment audit resulting in no findings. With thanks to all our employees for their dedication in maintaining and continually improving our Quality System.

Last week’s round-up;
10 -14 August 2020

Evaluation of the medicines for rare diseases and children legislation

On 11 August 2020, the EC published an evaluation of the EU orphan and pediatric regulations, adopted in 2000 and 2006, respectively. Following an evaluation comprising several steps, the regulations were analysed according to five criteria: effectiveness, efficiency, relevance, coherence; and EU added value. It was concluded that the regulations met their main objectives of increasing the number of products for patients with rare and paediatric diseases in the EU. Conversely, however, issues were recognised including: · Products may not be equally accessible across the EU or affordable to national health systems; · Circumstances may have changed since the regulations were introduced; · The regulations do not have instruments to counteract observed clustering of products leaving areas of unmet need, or to direct development to areas most relevant to children; · The concept of prevalence as a tool to receive orphan designation and the length of the 10-year market exclusivity period may need to be re-examined. Looking forward, it was noted that some of the issues identified are closely linked to and will be tackled by the Pharmaceutical Strategy for Europe.

https://lnkd.in/daqjhgh

EMA addresses risk evaluation, mitigation for nitrosamines

The EMA has updated its Q&A document on nitrosamine impurity testing for marketing authorisation holders. MAHs need to perform a risk evaluation to determine whether chemically synthesized active pharmaceutical ingredients are at risk of containing nitrosamines by 31 March 2021 (extended deadline). This same requirement has now been extended to biologicals, with a deadline of 1 July 2021. Biologicals considered particularly at risk include those containing chemically synthesized fragments, those where nitrosating reagents are added, and those packaged in nitrocellulose blister packs. The document includes further deadlines for confirmatory testing where applicable, as well as related variation submission requirements. It also delineates specific requirements for analytical methods to be used in testing, mitigation measures when nitrosamines are detected, and daily acceptable limits for various nitrosamines.

https://bit.ly/RealCMC-2XSGoCR

Tackling serious impurities

Discovery of N-nitrosamines in a variety of medicines over the last two years could have a much wider impact on pharmaceutical manufacturers and regulators than previously expected. The underlying issue in all N-nitrosamine contamination cases was inadequate control of impurities, and so European Union regulators want manufacturers and national regulators to take more effective action in tackling all potentially carcinogenic impurities in APIs and finished products. This decision arises from results published by a ‘lessons learnt’ group within the EU medicines licensing network. The group has proposed a variety of guidance reviews, including those relating to marketing authorization holders, finished product and API manufacturers, active substance master file and CEP holders. Updates to ICH M7 and the EU’s good manufacturing practice guidance have also been proposed.

https://bit.ly/RealCMC-2DNXhax

GMP inspectorate audits, Brexit stockpiling, and MHRA’s Covid-19 divergences

The EMA’s Mutual Recognition partners can now take part in audits of the GMP inspectorates of national authorities. MRA partners could previously participate in audits as observers and, from now on, will also be able to participate as co-auditors if they express an interest in doing so. However, MRA partners still won’t be able to serve as lead auditor, as this role is reserved for European groups. In other regulatory news, the UK government has asked industry to stockpile medicines ahead of the next Brexit deadline at the end of the year. The MHRA has also highlighted nine areas where its COVID-19 flexibilities diverge from EU policies. The list includes MHRA’s positions on qualified person declarations, the 30-day limit for type 1B variation replies, leaflet mock-ups and over-labelling.

https://bit.ly/RealCMC-2PL1LBi

Endotoxin levels in investigational cancer treatments

The US FDA has released new draft guidance on setting limits for endotoxins during the clinical trial process for parenteral oncology drugs intended for serious and life-threatening cancers. This new document provides risk-based guidance on endotoxin limits for investigational therapies that are used in early clinical trials in conjunction with other approved treatments or with other investigational medicines. Patients’ possible exposure to endotoxin levels exceeding USP recommendations may be considered an acceptable risk under appropriate circumstances.

https://bit.ly/RealCMC-3ipJZzX

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Last weeks round-up; 17 – 21 February 2020

NSAI ACHIEVES DESIGNATION TO THE MEDICAL DEVICE REGULATION

The National Standards Authority of Ireland (NSAI) has been approved for designation to the new Medical Device Regulations (MDR). This hugely significant achievement makes NSAI only the 11th notified body in the world to be designated to the new medical device regulation. Further information on this notable achievement can be found here < https://lnkd.in/dx5auvY>

As an NSAI certified ISO 9001:2015 company Real Regulatory congratulates the team at NSAI on the recent approval.

ICH GUIDELINES TO TAKE EFFECT IN EU BY END JULY 2020

EMA has announced that two ICH Guidances – ICH E9(R1) addendum on estimates < https://lnkd.in/dgU3jCr> and sensitivity analysis in clinical trials and ICH S5(R3) on reproductive toxicology < https://lnkd.in/dWApy26> – will take effect in EU on 30 July 2020. The E9(R1) addendum presents a framework for defining an appropriate estimate for a clinical trial and conducting sensitivity analyses.

While the S5(R3) guideline, ICH sets out recommendations for a harmonized approach to assessing nonclinical developmental and reproductive toxicity (DART) testing used to support clinical trials and drug approvals.

REGULATORY FRAMEWORK FOR ATMPS – PROPOSED ACTIONS STATUS UPDATE

EMA has published an updated status on the list of proposed actions to improve the regulatory framework for ATMPs. The complete list can be found under this link <https://lnkd.in/dvx_6RZ>.

Under line item 6, finalisation of the EMA guideline on investigational ATMPs is expected by Q4 2020. It is stated that ‘The Guideline will not change the competence of Member States to approve clinical trials but it will help create common standards for the assessment of these novel products.’ Under line item 7, in relation to the guideline ‘Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (CHMP/ GTWP/671639/2008)’, finalisation is expected by Q2 2020.

Europe as a Centre for Regulatory Excellence – The journey

Chair: Lorraine Nolan, Chief Executive, HPRA, Ireland

Panelists:

Lorraine Nolan welcomed attendees to Dublin and introduced the session, asking attendees to answer a few questions using the Menti.com mobile app, to show the demographics of the attendees (e.g., which area of regulatory affairs they work in and how many years of regulatory experience they have) and what the attendees saw as key developments going forward (real world evidence(RWE) and artificial intelligence (AI) were the top answers).

Pär Tellner gave the industry view regarding whether Europe is a centre for regulatory excellence. On the positive side, the EU review procedure is predictable with clear timelines; the EU Centralised Procedure (CP) system of having both a rapporteur and a co-rapporteur ensures continuity; the EU system is an example and inspiration for other regions, e.g., Eurasian Economic Union; and the EMA’s coordination role for joint HTA/regulator scientific advice (SA), Priority Medicines (PRIME) scheme and Regulatory Science Strategy to 2025 are great examples of regulatory excellence. However, there are also areas with potential for improvement: EU approval times are generally longer than for US and Japan; the perception amongst EFPIA companies is that the US FDA is more open to accepting data from complex clinical trials (CTs) and RWE (although no evidence that this is in fact true); there is insufficient consistency at all levels of the network, e.g., paediatrics; EMA SA timelines are too long at 4-6 months; and processes for drug-device combinations and biomarker validation need to be optimized. The risk is that new active substance submissions will be submitted first in US, Japan and China, with European submission only later in a second wave.

Representing the EMA, Anthony Humphries asked how can the EMA be future-proofed, and what should the agency be doing in the next 5 years? The EMA holds technology platform meetings with companies to find out what new technologies they are developing. EMA is trying to: foster innovation in CTs, e.g., methodological complexity, multiplicity and digital therapeutics; promote use of high quality real world data (RWD) with involvement of patients across the product life-cycle; encourage health technology assessment (HTA) preparedness for faster patient access; keep abreast of medical innovations in diagnosis, e.g., genomics and AI. The goal is to provide an environment that fosters innovation, not to set up hurdles, in order to ensure availability of safe and effective medicines.

Greet Musch provided a national competent authority (NCA) view, discussing the Heads of Medicines Agencies (HMA)-EMA regulatory framework common strategy, which focuses on four areas. First, innovation, which requires the medicines agencies to reach out to the medical technology sectors to develop a more holistic view of the different regulatory initiatives, e.g., interplays of CT Regulation with IVD Regulation; seek out critical expertise and focus on innovative CT designs. Second, availability/accessibility of medicines, which requires reaching out to HTA bodies, payers, health care providers and patient both from an early stage and during the product life-cycle; and enhancing international alignment. Third, use of data analytics and AI in decision making, with use of RWD/RWE and digitalization of CT and manufacturing processes. Fourth, sustainability and operational excellence of the regulatory network, with a leaner iterative process to enhance return on investment with innovation committees linking together existing groups, e.g., SAWP-CTFG-EUNetHTA, CTFG-PDCO; and development of NCAs as centres of excellence.

Florian Schmidt presented the European Commission view, admitting that there are challenges for the system now with new political leadership due in November 2019.  However, divergences are being addressed with medical devices being considered now also under the same DG with medicines and setting the dual priorities of supply of affordable medicines whilst still supporting innovation to keep the EU at the forefront of development.  Innovation is of no help if it doesn’t reach the patient, so access and availability are focus areas. The recent nitrosamines issue has raised the question of whether the EU quality system is strong enough, with more global diversity in supply introducing more risk. With the rise in ATMPs, drug/device combinations, use of AI in CTs and post-market, is the EU regulatory system still fit for purpose? These changes in paradigm must affect the regulatory framework.

During the panel discussion, the following key points emerged for future action to keep Europe a centre of regulatory excellence:

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