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  • Writer's pictureEJPPS

Updated: May 12, 2021

Review of Developments in GMP and the Regulation of Medicines August 2020

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Volume 25-3 B August-2020
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During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from Australian, EU, UK and USA regulatory authorities.

The topics covered in this edition of the “Update” include:

  • Action Plan on ATMPs

  • EDQM Highlights – 2019 annual report

  • EMA finalises opinion on presence of nitrosamines in medicines

  • ICH guideline M7 assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – Q&A Step 2b

  • Guideline on the quality of water for pharmaceutical use

  • EMA Annual activity report 2019

  • Implementation of the new Veterinary Medicines Regulation

  • European medicines agencies network strategy to 2025

  • Joint Audit Programme for EEA GMP inspectorates

  • MHRA planning for return to on-site Good Practice (GxP) inspections

  • MHRA A Practical example of applying Quality Risk Management in GDP – Transportation Risks

  • FDA prepares for resumption of domestic inspections with new risk assessment system

  • Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products

  • Setting endotoxin limits during development of investigational oncology drugs and biological products

  • GMP approach to overseas manufacturers of medicines and biologicals during the COVID-19 pandemic

  • TGA expectations for overseas manufacturing sites hosting remote inspections during the COVID-19 pandemic

  • Consultation on the new Therapeutic Goods Order 106 - Data matrix codes and serialisation of medicines




Action Plan on ATMPs

The European Commission services and the European Medicines Agency, in collaboration with the authorities of the Member States, have initiated a number of initiatives to improve the regulatory environment for ATMPs so as to facilitate the development and authorisation of these products in the EU for the benefit of patients. The actions presented in this document are wide-ranging and target challenges identified by various stakeholders at all stages of development, including manufacturing, early and later phases of development, marketing authorisation process and post-marketing setting. It is expected that the implementation of the proposed actions will increase the opportunity for patients to be treated with novel therapies (through enrolment in clinical trials and authorisation of new products). Moreover, an improved regulatory framework will also contribute to promoting innovation, investments and competitiveness of the EU biotechnology sector, whilst striving to ensure patient access.


EDQM Highlights – 2019 annual report

The European Directorate for the Quality of Medicines & HealthCare’s 2019 annual report is now available, providing a comprehensive overview of our activities in 2019 and information on our achievements and events.

The highlights of 2019, another very productive and successful year for the EDQM, include:

  • the Ph. Eur. Commission continued to provide Ph. Eur. users with up-to-date and science-based quality standards by adopting 257 new or revised Ph.Eur. texts;

  • the Ph. Eur. portfolio of reference standards continued to grow;

  • a secondary site to house the EDQM’s contingency stocks of reference standards was inaugurated;

  • the procedure for the certification of suitability to the Ph. Eur. monographs (CEPs) again demonstrated its added value for regulatory authorities: with 254 new certificates issued, the number of valid CEPs is now over 5200;

  • work-sharing within the network of European Official Medicines Control Laboratories (OMCLs) allowed members to cover a broad range of products on the market and address emerging risks to public health;

  • milestones were reached in pharmaceutical care, such as the adoption of a resolution on the promotion and implementation of pharmaceutical care in Europe by the Council of Europe Committee of Ministers;

  • the first two monographs and two general texts of the European Paediatric Formulary were adopted and now provide healthcare professionals with useful guidance;

  • trusted and ethical safety and quality standards for the collection, preparation, storage, distribution and appropriate use of blood components for blood transfusion and for the transplantation of organs, tissues and cells continued to be proposed, and the of the 4th edition of the Guide to the quality and safety of tissues and cells for human application was published;

  • work related to the co-ordination of market surveillance studies and proficiency testing schemes in the area of quality control for cosmetics continued, along with efforts to update existing and develop new standards in the field of food contact materials;

  • the EDQM continued its action and efforts to address the presence of N-nitrosamines in active substances and medicines and supported regulatory authorities at national, international and EU level in this field. Regular updates were published on the EDQM website.

Pharmeuropa Volume 32 No. 3, July 2020

Users of CEPs are invited to provide comments on draft monographs published in Pharmeuropa 32.3 before 30 September 2020.


EMA finalises opinion on presence of nitrosamines in medicines

EMA’s human medicines committee (CHMP) has issued an opinion requiring companies to take measures to limit the presence of nitrosamines in human medicines as far as possible and to ensure levels of these impurities do not exceed set limits.

The measures will ensure that nitrosamines are either not present or are present below levels identified to protect public health.

Companies will be required to have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, improve their manufacturing processes.

Companies will also have to evaluate the risk of nitrosamines being present in medicines and carry out appropriate tests if a risk is identified.

Detailed information for companies, including timelines, will soon be available in updated documents on EMA’s nitrosamine impurities webpage. In the meantime, companies should continue to follow current instructions.

It should be noted that on the above EMA nitrosamine impurities webpage that the CHMP adopted a scientific opinion in June 2020, which recommended reviewing biological medicines in addition to medicines containing chemically synthesised active substances. For biological products the BWP concluded that there is only a very low risk of nitrosamines being present as impurities. At higher risk would be biological products containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances should be considered, or biologicals packaged in blister packs containing nitrocellulose. Consideration should be given to extending the risk evaluation to classes of biological product using processes where nitrosating reagents are deliberately added. The CHMP agrees with the BWP advice and considers that a risk evaluation/risk assessment for biological medicinal products should be performed taking into consideration the above-mentioned risk factors.

[significant medicines shortages have already been caused by these nitrosamine impurities. This is an area where knowledge is still developing and where Quality Risk Management has and will continue to have an important role to play in the evaluation of current and future process design. MBH]

ICH guideline M7 assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – Q&A Step 2b

Since the ICH M7 Guideline was finalized, worldwide experience with implementation of the recommendations for DNA reactive (mutagenic) impurities has given rise to requests for clarification relating to the assessment and control of DNA reactive (mutagenic) impurities. This Q&A document is intended to provide additional clarification and to promote convergence and improve harmonization of the considerations for assessment and control of DNA reactive (mutagenic) impurities and of the information that should be provided during drug development, marketing authorization applications and/or Master Files. The scope of this Q&A document follows that of ICH M7. “Applicant” is used throughout the Q&A document and should be interpreted broadly to refer to the marketing authorization holder, the filing applicant, the drug product manufacturer, and/or the drug substance manufacturer.

Guideline on the quality of water for pharmaceutical use

This guideline replaces the Note for Guidance on quality of water for pharmaceutical use (CPMP/QWP/158/01, EMEA/CVMP/115/01) originally adopted in May 2002, and the CPMP Position Statement on the Quality of Water used in the production of Vaccines for parenteral use (EMEA/CPMP/BWP/1571/02 rev.1). The note for guidance has been updated to reflect the following changes in the European Pharmacopoeia:-

  • revised monograph for Water for Injections (0169) allowing the possibility to use methods other than distillation for producing water of injectable quality;

  • new monograph for Water for preparation of extracts (2249); suppression of the monograph for Water, highly purified (1927). The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.

The new guideline comes into effect 1 February 2021.

In addition, a history of the topic can be viewed on the EMA webpages.

EMA Annual activity report 2019

The consolidated annual activity report provides an overview of the activities and achievements of the European Medicines Agency (EMA) in 2019. It is a report of the EMA Executive Director and is a key component of the strategic planning and programming cycle and the basis upon which the EMA Executive Director takes his responsibility for the management of resources, and the achievement of objectives. It also allows the EMA Executive Director to decide on the necessary measures in addressing any potential management and control weaknesses identified. The report 2019 comprises four main parts and annexes, as follows:

Part I: Key achievements in 2019. This section provides an overview of the Agency's major achievements.

Part II: Work programme implementation.

Part III: Organisational management and internal control.

Part IV: Management assurance.

In the annexes, the report provides information on the EMA establishment plan, human and financial resources used by activity, the organisational chart, project implementation, and further specific annexes related to Part II and Part III of the report

Implementation of the new Veterinary Medicines Regulation

New sections have been added to the EMA webpage covering implementation of the VMR. These relate to :-

GDP for Active Substances;

GDP for Veterinary Medicinal Products; and

The format of data collected on use of antimicrobial products.

Heads of Medicines Agencies (HMA)

European medicines agencies network strategy to 2025

This draft strategy details how the European medicines agencies’ network can continue to enable the supply of safe and effective medicines that meet patients’ needs in the face of challenges posed by ever-accelerating developments in science, medicine, digital technologies, globalisation as well as emerging health threats, such as the COVID-19 pandemic. It addresses how HMA intends to ensure that it continues protecting public health at a time of rapid change.

The document outlines six strategic focus areas

  • Availability and accessibility of medicines

  • Data analytics, digital tools and digital transformation

  • Innovation

  • Antimicrobial resistance and other emerging health threats

  • Supply chain challenges

  • Sustainability of the Network and operational excellence

The strategy is intended to be a living document which will be periodically reviewed, and detailed actions to implement it will be further developed by EMA and the national authorities in their multi-annual work plans. For most of these actions the work will be shared between national authorities and EMA and will involve close collaboration. Following the public consultation, which runs for 2 months until 4 September 2020 via an online questionnaire, comments from stakeholders and the public will be analysed and considered in the final draft of the document. [The document is lengthy (46 pages) but essential reading to help you understand and keep abreast of regulatory needs / direction MBH ]

Joint Audit Programme for EEA GMP inspectorates

Three documents within this programme have been updated. These are:-

JAP Programme

The scope of the Joint Audit Programme (JAP) is to verify the implementation of relevant provisions of European Union (EU) legislation into national laws, authorisation/licensing system for manufacturers and importers, GMP compliance certification, administration of inspections, inspectorate, resources, complaints, rapid alerts including laboratory support, enforcement and internal quality assurance. The JAP covers all European Economic Area (EEA) GMP inspectorates in the field of medicinal products for human and veterinary use, including active substances. The audit programme forms an essential part of the GMP inspectorate’s quality system as referred to in the legislation (Directive 2003/94/EC) and adopted by GMP inspectorates as part of the Compilation of Union Procedures on Inspections and Exchange of Information. It ensures harmonised inspection standards and a harmonised approach to practical interpretation of GMP on the basis of European Union legislative requirements to support mutual recognition of inspection outcomes. Additionally, and in order to satisfy requirements laid down in mutual recognition agreements (MRAs) and other legal agreements between the EU and some third countries, all member states have agreed to implement harmonisation of inspection practices and compliance procedures. This is particularly important in order to preserve confidence in the GMP compliance systems among MRA and other partners as agreed in the MRA and partners’ maintenance programmes.

JAP Procedure

This procedure describes how the Joint Audit Programme (JAP) and its audits are performed. It covers the planning for audits and the audit process of competent authorities (CAs) in charge of the GMP compliance programme as detailed in the ‘Evaluation Guide for GMP Regulatory Compliance Programme - Audit Checklist’ (JAP Audit checklist) as well as the JAP Observed inspection checklist.

JAP audit report template



Planning for return to on-site Good Practice (GxP) inspections

As the UK Government and Devolved Administrations gradually ease the restrictions on travel / social distancing/ return to workplaces, MHRA is making careful preparations for a safe return to normal UK on-site inspection scheduling.

MHRA has been engaging with industry trade associations and the NHS to discuss the practical arrangements that may be required to facilitate on-site inspection starting in September and scaling up to a full programme from October 2020.

Inspection conduct will vary according to the requirements of each GxP area and may include a hybrid model of on-site and off-site activities that support a single inspection cycle.

A Practical example of applying Quality Risk Management in GDP – Transportation Risks

Distribution of medicines has inherent risks, and by applying QRM it is possible to identify and define the risks, possibly remove some of them and create the means to improve detection of risk events and thereby reduce their impact. It can also help identify what is an acceptable level of risk.

A summary of inherent risks and their criticality will assist managers to be mindful of risks in different areas of their organisation thereby showing consequential change in risk caused by an action, and can also provide a benchmark of current risk level. Many companies present such summaries as a spreadsheet which assists communication, an essential part of QRM. The summary should be regularly re evaluated and potential changes assessed during quality management review meetings.

It is rare to find sound scientific justification for acceptance of a load subject to an excursion, and in the uncommon instances where a supplier or customer contacts the marketing authorisation holder for stability information, it is often not directly comparable to the excursion experienced. Unfortunately, the most common reason for accepting a consignment with a temperature excursion is purely commercial, which may put patients at risk and undermines any risk management carried out by the company. In some cases of quality risk management, attempts were made to inappropriately apply mean kinetic temperature to underestimate impact rather than develop good control and preventive measures.

United States of America

The US Food and Drug Administration (USFDA)

FDA prepares for resumption of domestic inspections with new risk assessment system

Despite pausing on-site surveillance inspections in the U.S. in March, FDA investigators have conducted mission critical inspections and other activities to ensure FDA-regulated industries are meeting applicable FDA requirements. FDA has successfully used a number of tools as part of the agency’s risk-based approach to ensuring quality, including remote assessments and import alerts as well as other compliance requirements. At this time, FDA is working toward the goal of restarting (domestic) on-site inspections during the week of July 20. However, resuming prioritized domestic inspections will depend on the data about the virus’ trajectory in a given state and locality and the rules and guidelines that are put in place by state and local governments. In order to move to the next phase, there must be downward trends in new cases of COVID-19 and hospitalizations in a given area. FDA’s ability to resume is also affected by other services that have been curtailed by the pandemic, such as public transportation. The availability of these services will be an important factor in how we determine resuming domestic inspections. The FDA has also determined that, for the foreseeable future, prioritized domestic inspections will be pre-announced to FDA-regulated businesses. This will help assure the safety of the investigator and the firm’s employees, providing the safest possible environment to accomplish our regulatory activities, while also ensuring the appropriate staff from the inspected party are on-site to assist FDA staff with inspection activities.

Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products

The last few decades have seen an increasing demand in various health care settings for solid oral dosage form drug products repackaged into unit-dose containers, which hold a quantity of drug for administration as a single dose. The increase in unit-dose repackaging has led to questions regarding stability studies and appropriate expiration dates for these repackaged products. This guidance describes the circumstances under which FDA generally does not intend to take action regarding required stability studies for these repackaged products and appropriate expiration dates under those circumstances.

This guidance addresses repackaging of prescription and over-the-counter solid oral dosage form drugs into unit-dose containers by commercial pharmaceutical repackaging firms that are required to register with FDA under section 510 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and to comply with current good manufacturing practice (CGMP) regulations in 21 CFR parts 210 and 211.

Pregnancy, lactation, and reproductive potential: labeling for human prescription drug and biological products

This guidance is intended to assist applicants in complying with the content and format requirements for the Pregnancy, Lactation, and Females and Males of Reproductive Potential (PLLR) subsections of labeling for human prescription drug and biological products. This guidance provides information and recommendations for preparing subsections 8.1 Pregnancy, 8.2 21 Lactation, and 8.3 Females and Males of Reproductive Potential of the USE IN SPECIFIC POPULATIONS section.

The PLLR established the Females and Males of Reproductive Potential subsection of labeling and requires information for these populations when there are recommendations or requirements for pregnancy testing and/or contraception before, during, or after drug therapy, and/or there are human and/or animal data suggesting drug-associated effects on fertility and/or pre-implantation loss effects. The recommendations and/or requirements for pregnancy testing and/or contraception may be based on concerns for potential or demonstrated adverse developmental outcomes associated with drug exposure during pregnancy.

Setting endotoxin limits during development of investigational oncology drugs and biological products

New approvals in oncology often build on prior success by adding new drugs to current regimens or by combining products in a novel treatment regimen, creating new multidrug regimens that may have greater efficacy.

This guidance describes FDA’s recommendations to investigational new drug sponsors for setting endotoxin limits during the development of investigational drugs intended for use in combination with other approved drugs or for the co-development of two or more investigational drugs. The scope of this guidance is limited to anticancer drugs, including combination products under 21 CFR Part 3, as described further in this guidance and administered parenterally (except for intraocular administration) to treat serious and life-threatening cancers based on histology or stage of disease. This guidance does not apply to the development of drugs for adjuvant or neoadjuvant treatment or for cancer subtypes that can be cured or where prolonged survival can be achieved with available therapy.



GMP approach to overseas manufacturers of medicines and biologicals during the COVID-19 pandemic

The COVID-19 pandemic has created many challenges to the ongoing GMP regulation of medicine and biological manufacturers.

Following the suspension of overseas GMP inspections and QMS audits, a significant amount of consideration was given to the appropriate level of regulatory oversight required to maintain an assurance of product quality without requiring wholesale changes to existing processes.

These considerations needed to be agile yet sustainable as the length of time that international travel restrictions remain in place is difficult to predict.

For the latest developments see the information “boxes” relating to GMP inspections and GMP clearances on the TGA website.

TGA expectations for overseas manufacturing sites hosting remote inspections during the COVID-19 pandemic

The TGA has made some very specific and detailed requirements for conducting remote inspections. These specifically relate to the nomination of an authorised responsible person to be the Remote Inspection Host. This authorised person must have the required authority and IT support to ensure a smooth remote inspection process can take place. TGA Inspection staff will use the Remote Inspection Host as their point of contact for all communication in relation to the remote inspection for the site.

Also, to prepare for a remote inspection the manufacturer should organise to have pre-recorded videos of the site and operations so that the inspectors can be presented with a virtual tour of GMP relevant areas.

If the manufacturer has electronic systems for QMS databases such as complaints, deviations, OOS/OOT and other GMP relevant areas then it is requested to organise guest remote read only logins to the QMS databases for inspectors’ use at the time of inspection.

The TGA will conduct the inspection in English. The manufacturer must have interpreters available, for each inspector on the Inspection Team, who have both excellent technical knowledge and English skills.

[Some of these requirements appear quite far reaching and may be difficult / take time to arrange.- so like the scouting movement “be Prepared” MBH]

Consultation on the new Therapeutic Goods Order 106 - Data matrix codes and serialisation of medicines

The Therapeutic Goods Administration (TGA) has drafted a Therapeutic Goods Order (TGO 106) which makes requirements for serialisation and the use of data matrix codes on the labels of certain medicines in the Australian supply chain. This consultation closes on 13 August 2020.

And finally…

Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.

We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.


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