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Review of Developments in GMP and the Regulation of Medicines September 2019

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Vol 24-4 September-2019
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  • Q&A on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country.

  • Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities

  • Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines

  • EMA/FDA analysis shows high degree of alignment in marketing application decisions between EU and USA

  • MHRA Falsified Medicines and the supply chain (part 2)

  • MHRA Analytical Quality by Design (AQbD): Q&A

  • HHS announces new action plan to lay foundation for safe importation of certain prescription drugs

  • Child-Resistant Packaging statements in drug product labeling

  • Information about immune globulin (human) product shortage

  • Regulatory harmonization and convergence

  • Biological Product and HCT/P deviation reports annual summary for fiscal year 2018

  • Oncology therapeutic radiopharmaceuticals: nonclinical studies and labeling recommendations

  • Patent certifications and suitability petitions (ANDAs)

  • TGA actions following 2018 stakeholder surveys

  • Mandatory information required in advertising for therapeutic goods

  • Swissmedic laboratory publishes updated test method for nitrosamines in sartans

  • Names of liposomal medicines to be changed to avoid medication errors




Q&A on the exemption from batch controls carried out on ATMPs imported into the European Union from a third country.

This Q&A covers four scenarios: -

  1. What are the obligations of the Qualified Person (QP) regarding testing of batches for ATMPs imported into EU?

  2. In which cases can the exemption from EU batch retesting for imported ATMPs be granted?

  3. Which data should be submitted in the marketing authorisation application to the EMA in order to justify the exemption from batch re-testing in the EU of imported ATMPs?

  4. What are the obligations of the Qualified Person for the batch release of imported batches exempted from re-testing in the EU?

Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities

On 31 January 2019, EMA recommended that companies making sartan blood pressure medicines (also known as angiotensin II receptor blockers) review their manufacturing processes so that they do not produce nitrosamine impurities.

Before June 2018, NDMA and NDEA were not among the impurities identified in sartan medicines and were therefore not detected by routine tests. It is now known that these impurities can form during the production of sartans that contain a specific ring structure known as a tetrazole ring under certain conditions and when certain solvents, reagents, and other raw materials are used. In addition, it is possible that impurities were present in some sartans because manufacturers had inadvertently used contaminated equipment or reagents in the manufacturing process.

Companies must now take measures to avoid the presence of these impurities and carry out rigorous testing of their products.

Companies will have a transition period to make any necessary changes, during which strict temporary limits on levels of these impurities will apply. After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of these impurities before they can be used in the EU.

Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines

The Safety Working Party (SWP) has critically assessed the available experimental toxicological data on NMBA, DIPNA and EIPNA. Only for NMBA and DIPNA could toxicological data be retrieved from public sources. For EIPNA no data have been found. The SWP considers the experimental toxicological data as insufficient to derive protective substance specific AI levels for NMBA, DIPNA and EIPNA. The carcinogenicity studies for NMBA and DIPNA do not provide appropriate numbers of dose groups or group size to calculate robust TD50 values. Mutagenicity data are also insufficient. The only conclusion that can be drawn is that NMBA and DIPNA are potent carcinogens in rats.

In line with the methodology suggested in ICH M7 chapter 7.5, carcinogenicity data from closely related structures may be used on a case-by-case basis. To identify closely related structures, an expert structure activity relationship analysis (SAR) was performed. This analysis suggested that NDMA and NDEA data could be used to derive AI levels for NMBA and also for DIPNA and EIPNA based on their close SAR and the alkyldiazonium ions formed. According to Sulc et al. (2010) alkyl Nnitrosamines are bio-transformed via α-hydroxylation with the release of carbonyl compounds such as formaldehyde to the corresponding alkyldiazonium ions being responsible for covalent modification of DNA.

Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines

The SAR analyses provide plausible arguments for close relationship of NMBA to NDMA and of DIPNA/EIPNA to NDEA. The data of the most closely related compounds were used as a point of departure for calculation of AI levels. Based on the TD50 data for NDEA (for DIPNA and EIPNA) and NDMA (for NMBA) in rats, compound specific AI levels associated with a theoretical excess cancer risk of 1:100,000 when exposed daily for a lifetime have been calculated according to ICH M7 (R1). The limits are given in the table below together with corresponding parts per million (ppm) values in the maximum daily dose of each sartan.

EMA/FDA analysis shows high degree of alignment in marketing application decisions between EU and USA

EMA and the US FDA are aligned in more than 90% of marketing authorisation decisions for new medicines. The high rate of convergence in the authorisation of new medicines at EMA and the FDA is the result of expanded investment in dialogue and cooperation since 2003 and has fostered alignment between the EU and the US with respect to decisions on marketing authorisation, while both agencies evaluate applications independently of each other.

Some differences were observed in the clinical data due to the difference in timing of submissions (more applications were submitted to the FDA before they were submitted to EMA). Compared to the FDA, EMA often reviewed applications including additional clinical trials or, particularly for oncology medicines, more mature data from the same clinical trial. In those instances, EMA was more likely than the FDA to grant standard approval, a broader indication, or use of a medicine as first-line therapy.


Falsified Medicines and the supply chain (part 2)

In this post Tracy Moore of MHRA shares the experience gained from recent events to assist companies and individuals efforts to comply with the Falsified Medicines Directive (FMD) requirements.

It is important to know who you are dealing with and how to stay vigilant with respect to some of the pitfalls.

During the 2018 GDP Symposium, Naseem Hudroge and Bruce Figg from the MHRA Enforcement section talked about the illegal diversion of benzodiazepines and Z drugs These drugs (the names of which usually begin with the letter 'Z') are used in the treatment of sleep problems) The presentation covered:

  • the investigations conducted

  • emerging trends

  • awareness of social engineering

  • phishing and email spoofing.

The information provided in the presentation can also be used in the general context of ensuring the validity of the distribution channels and avoiding being hoodwinked by a supplier into believing a different reality.

Other recent MHRA posts have described

  • some of the approaches taken by criminals who use deception to obtain stock or divert falsified medicine back into the legitimate supply chain.

  • measures that wholesalers can take to reduce the chance of dealing with unauthorised suppliers or customers. Aside from deception, being left in a position where you have to recall falsified medicines from the market can be reputationally and financially damaging.

In MHRA’s experience, after an event involving falsified products, goods-in staff often report that they had suspicions or thought that something unusual was occurring. Staff should always be alert to any unusual activities and have a formal mechanism by which they can raise their concerns.

(There is lots of good information in this blog – make sure you take a good look through it. - The current shortages of certain medicines such as HRT drugs in the UK could present opportunities for criminal activity or could even be as a result of such activity. Could some of the reported “commercially sensitive manufacturing issues” causing the shortages even be as a consequence of non compliance with the requirements of falsified medicines directive itself? MBH.)

Analytical Quality by Design (AQbD): Q&A

A new post, “Analytical Quality by Design (AQbD): Q&A” has been published on the MHRA Inspectorate blog. The blog details questions and answers arising from discussions with scientists from the British Pharmacopoeia, as to why this consultation may prove vital to the future of pharmacopoeial standards and why stakeholders should take the opportunity to have their say although notification here or via the blog is rather ill timed as 31 Aug 2019 saw the close of the consultation period.

Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management. As a concept, it aims to assure the quality of medicines by using enhanced approaches to design, development and manufacture of medicinal products. The application of QbD principles to analytical methods is being explored by industry, regulators and academia.

The purpose of the consultation is to understand the views of Agency stakeholders on the application of AQbD principles to pharmacopoeial standards and includes a series of examples to illustrate the potential models for inclusion in the pharmacopoeia.

United States of America

The US Food and Drug Administration (USFDA)

HHS announces new action plan to lay foundation for safe importation of certain prescription drugs

The U.S. Department of Health and Human Services (HHS) has announced that HHS and the U.S. FDA are publishing a Safe Importation Action Plan that outlines two potential pathways that would lay the foundation for the safe importation of certain drugs originally intended for foreign markets.

The Action Plan outlines the government’s intention to pursue two pathways to allow safe drug importation from foreign markets:

  • Through a notice of proposed rulemaking (NPRM), HHS and FDA would propose to rely on the authority under current federal law (Federal Food, Drug, and Cosmetic Act (“FD&C Act”) Section 804) that would, when the rule is finalized, authorize pilot (or demonstration) projects developed by states, wholesalers or pharmacists and submitted for HHS review, outlining how they would import certain drugs from Canada that are versions of FDA-approved drugs that are manufactured consistent with the FDA approval. The NPRM would include conditions to ensure the importation poses no additional risk to the public’s health and safety and that the demonstration projects would achieve significant cost savings to the American consumer.

  • Through guidance, FDA would provide recommendations to manufacturers of FDA-approved drugs who seek to import into the U.S. versions of those drugs they sell in foreign countries. Under this pathway, manufacturers would use a new National Drug Code (NDC) for those products, potentially allowing them to offer a lower price than what their current distribution contracts require. To use this pathway, the manufacturer or entity authorized by the manufacturer would establish with the FDA that the foreign version is the same as the U.S. version and appropriately label the drug for sale in the U.S. This pathway could be particularly helpful to patients with significantly high cost prescription drugs. This would potentially include medications like insulin used to treat diabetes, as well as those used to treat rheumatoid arthritis, cardiovascular disorders, and cancer.

(This is part of President Trump’s proposals to reduce the cost of medicines to patients in the USA. It appears in some ways similar to the parallel imports processes in the EU. Potentially it will have both positive and negative effects. “parallel importers” will probably be all for it, whilst US based companies or those cited elsewhere but already approved for USA supply may see their profits being eroded and the potential for falsified medicines increased. Supply demand from a large market such as the USA may well also cause shortages in Canada or other markets where supply originates. MBH)

Child-Resistant Packaging statements in drug product labeling

This final guidance is intended to assist applicants, manufacturers, packagers, and distributors who choose to include child-resistant packaging (CRP) statements in their drug product labeling. The guidance discusses what information should be included to support CRP statements in labeling for new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and supplements to these applications. In addition to recommendations for labeling of prescription drug products, this guidance also includes recommendations for labeling both for nonprescription drug products approved under an NDA or ANDA and those that are marketed under the Over-the Counter (OTC) Drug Review. This guidance is intended to help ensure that such labeling is clear, useful, informative, and, to the extent possible, consistent in content and format.

In 1970, the Poison Prevention Packaging Act (PPPA) was enacted to protect children under 5 years of age from unintentional exposure to household substances including food, drugs, and cosmetics. Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug that has packaging or labeling that is in violation of a regulation issued pursuant to section 3 or 4 of the PPPA is deemed to be misbranded. FDA was responsible for enforcing the PPPA until 1973, when jurisdiction was transferred to the U.S. Consumer Product Safety Commission (CPSC). Because of FDA’s authority to regulate labeling for prescription and nonprescription drug products, if firms choose to make statements in their labeling for such products about childresistant packaging, such statements must comply with FDA’s statutory and regulatory requirements.

CPSC’s regulations list “special packaging standards” (also referred to herein as childresistant packaging, or CRP) for a wide range of household products, including most oral prescription drugs and many nonprescription drug products. There are different ways to make packaging child-resistant, with the most common forms being a child-resistant closure (e.g., a “safety cap”) and certain unit-dose blister packaging (e.g., puncture-resistant and peel-push blisters. It should be noted that “child-resistant” should not be equated with “child-proof,” because CRP is not designed to completely eliminate the possibility of an accidental pediatric ingestion. It can only impede access to harmful products and is recognized by public health experts as only one component of preventing these events.

In this guidance, FDA recommends text that may be appropriate to consider when including CRP statements in the prescribing information, in the patient information, on carton labeling and container labels for prescription drug products, and in the drug facts labeling and on carton labeling and container labels for nonprescription drug products.

Information about immune globulin (human) product shortage

FDA monitoring confirms that, despite increased supply of immune globulin (IG) products in recent years, the demand for IG product has also increased over that same time and there is an ongoing shortage of Immune Globulin (Intravenous) (IGIV) and Immune Globulin (Subcutaneous) (IGSC) products in the United States. This shortage could impact patient care. In the setting of the increased demand for IG, other factors that ordinarily might not impact availability may have a greater effect. These could include uneven product distribution across different localities, logistics of contractual obligations, production delays, and other factors.

FDA does not have legal authority to require a manufacturer to begin producing, continue producing, or increase their production of drugs. However, FDA does work with manufacturers whenever possible to help mitigate shortages when we learn of them. The Agency is working very closely with applicants/manufacturers to help mitigate the supply situation for IG products as best as possible. It is also working with industry in exploring ways to improve the manufacturing yield of IG products, which are derived from donor plasma.

Regulatory harmonization and convergence

The term “regulatory harmonization” can have different definitions depending on the context of its usage. One definition that is applicable to those efforts is: the process by which technical guidelines are developed to be uniform across participating authorities. “Regulatory convergence,” on the other hand, represents a process whereby the regulatory requirements across countries or regions become more similar or “aligned” over time as a result of the gradual adoption of internationally recognized technical guidance documents, standards and scientific principles, common or similar practices and procedures, or adoption of regulatory mechanisms that might be specific to a local legal context but that align with shared principles to achieve a common public health goal. It does not necessarily represent the harmonization of laws and regulations, which is not a prerequisite for allowing the alignment of technical requirements and greater regulatory cooperation. USFDA engages in a range of explicit harmonization initiatives as well as convergence activities.

Biological Product and HCT/P deviation reports annual summary for fiscal year 2018

FDA requires reporting of certain deviations and unexpected events in manufacturing in accordance with 21 CFR 600.14, 606.171 or 1271.350(b). The following manufacturers, who had control over the product when an event associated with manufacturing (deviation or unexpected event) occurred, are required to submit Biological Product Deviation (BPD) reports to the Center for Biologics Evaluation and Research (CBER), if the safety, purity, or potency of a distributed product may be affected:

  • Manufacturers of licensed biological products other than blood and blood components (licensed non-blood) who hold the biological product license [21 CFR 600.14];

  • Licensed manufacturers of blood and blood components, including Source Plasma [21 CFR 606.171];

  • Unlicensed registered blood establishments [21 CFR 606.171]; and

  • Transfusion services [21 CFR 606.171].

In addition, manufacturers of nonreproductive Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) regulated by FDA solely under section 361 of the Public Health Service Act and 21 CFR Part 1271 [21 CFR 1271.350(b)] are required to submit HCT/P deviation reports to CBER, if the deviation or unexpected event involving a distributed product is related to a Core Current Good Tissue Practice requirement [21 CFR 1271.150(b)] and to the prevention of communicable disease transmission or HCT/P contamination.

This annual summary report provides an overview of the reports received during the fiscal year, including detailed information regarding the number and types of deviation reports received. Each firm responsible for reporting biological product and HCT/P deviations should use this information in evaluating their own deviation management program. The summary provides combined data received over the last three fiscal years to compare data and highlight changes

Oncology therapeutic radiopharmaceuticals: nonclinical studies and labeling recommendations

The purpose of this guidance is to provide information to assist sponsors in the design of an appropriate nonclinical program for the development of radiopharmaceuticals to treat cancer — also known as oncology therapeutic radiopharmaceuticals — and to provide recommendations for certain aspects of product labeling. For the purpose of this guidance, a therapeutic radiopharmaceutical is a product that contains a radionuclide and is used in patients with cancer to treat the disease or palliate tumor-related symptoms (e.g., pain). Recommendations in this guidance are applicable to products that are administered systemically and undergo alpha, beta, and/or gamma decay.

This guidance is specific to therapeutic radiopharmaceuticals for oncology indications and covers topics that are not addressed in current FDA or International Council for Harmonisation (ICH) guidance, such as nonclinical studies in support of first-in-human (FIH) trials and approval.

Patent certifications and suitability petitions (ANDAs)

FDA aspires to continually improve its pre-ANDA (abbreviated new drug application) interactions with applicants. To facilitate these interactions and keep stakeholders as informed as possible, the agency regularly publishes information on suitability petitions and Paragraph IV patent certifications.



TGA actions following 2018 stakeholder surveys

The TGA conducts regular stakeholder surveys to hear from stakeholders about where it is doing well and where it can improve. On 29 Aug 2019 it published a table describing some of its actions following the stakeholder surveys of June 2018.

Mandatory information required in advertising for therapeutic goods

Perhaps linked to one of the items in the above table, a decision tree has been designed to help identify what information must be included when advertising therapeutic goods to the public in order for the advertising to comply with the Therapeutic Goods Advertising Code (No.2)2018 (the Code).

This information only applies to advertising more broadly. It does not capture labels or packaging, consumer medicine information leaflets, or patient information leaflets, the content of which is specified in other legislation. It also does not apply to 'picture / price /point-of-sale' advertisements - i.e. advertisements with a packshot, price and where the product can be purchased with no therapeutic claims visible or implied.

The decision tree provides the minimum set of information required in an advertisement under the Code, based on the type of therapeutic good and the type of advertisement.

(Readers might ask “What has marketing got to do with GMP?) In my past experience I have seen examples where activity of the marketing arm of a company has resulted in the wider company receiving a Warning Letter or similar missive from a different regulator. I believe that there should be no disconnects for Quality across a company. A digression or bad reputation gained by one part of the company reflects across the company as a whole. MBH


Swissmedic laboratory publishes updated test method for nitrosamines in sartans

Ever since sartan-containing medicines had to be recalled from the market in the summer and autumn of 2018 due to nitrosamine contamination, Swissmedic's own lab, OMCL (Official Medicines Control Laboratory), has been testing sartans with a critical chemical structure for nitrosamines. The test method which the lab developed especially for this purpose has now been refined in order to further improve the sensitivity of testing for nitrosamine contamination.

The test method (first published in mid-December 2018) that has now been upgraded is used to determine whether the amounts of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) contained in valsartan and related sartans are above or below the safety limit The method is based on the use of gas chromatography–mass spectrometry (GC-MS).

The updated test method (31_PV_169) for measuring the permissible amounts of NDMA and NDEA is more robust and sensitive than the original one.


Names of liposomal medicines to be changed to avoid medication errors

Following a number of reports of serious medication errors, some leading to death, and after consultation with EMA’s safety committee the following actions were agreed to reduce the risk of mix-up between these medicines:

In section 1 of the summary of product charateristics (SmPC), the qualifier 'liposomal' or 'pegylated liposomal' should be added after the invented name and before the strength. This is in line with the standard practice for qualifiers.

In those cases where a medicine is approved with an international non-proprietary name (INN)+company or trademark' name, the qualifier 'liposomal' or 'pegylated liposomal' will be placed between the INN and the company name or trademark in section 1 of the SmPC.

The currently existing EDQM standard term ‘dispersion’, which includes liposomes in its definition, should be used consistently throughout the product information.

Marketing authorisation holders of medicines with liposomal and pegylated liposomal delivery systems are requested to submit an A.2.a variation before the end of September 2019 to update their product name in line with the recommendation.

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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