Stability Testing related News – Vol.7

◆  EU GMP Non-Compliance Report might lead to FDA Import Stop in future (11-Apr-17 ECA)

The new MRA Agreement between the EU and the USA on the mutual recognition of GMP inspections is being discussed in depth. One shouldn’t conclude though that the inspection pressure would decrease now because of the recognition of EU inspections. There is a series of exceptions to look out for. The FDA will first ask the competent authority of the EU when the last GMP inspection was performed at a site in question and which GMP deficiencies were found. If no recent inspection report is available (e.g. the inspection hasn’t been performed recently), the FDA can either request a further inspection (Article 10) or perform an inspection itself. In the MRA Agreement, Article 11 states: “Within 15 calendar days of receipt of the request, the recognized authority shall acknowledge receipt and confirm whether it will conduct the inspection in accordance with the requested timelines”… further, it is stated that: “For greater certainty, if the recognized authority indicates that it will not conduct the inspection, the requesting authority has the right to conduct its own inspection of the manufacturing facility and the requested authority has the right to join the inspection.”

Beside the fact that the FDA will perform its own inspections in the cases mentioned above, the future consequences of an EU GMP inspection for the US market should also be considered. Article 8 “Recognition of inspections” states: “For purposes of this Annex, to accept an official GMPs document means to rely on the factual findings in such document.” A GMP Non-Compliance Report is also an official GMP document. If an EU authority declares a GMP Non-Compliance status – among other things in the EudraGMDP – the FDA will use this assessment and take measures against the facility in question. In some cases, those measures might lead to an import alert, in other words to an import stop for the US market.

There are still substantial questions with regard to which EU GMP inspectorates will be recognised as of the 1st of November, for there is no list with the recognised authorities yet. According to Article 19: “If, by 1 November 2017, the FDA has not completed assessments under this Annex of at least eight Member State authorities for human pharmaceuticals listed in Appendix 2, despite having received complete capability assessment packages from those authorities as specified in paragraph II.A.1 of Appendix 4 in accordance with the schedule set out in Appendix 5, application of the Articles referred to in paragraph 2 shall be postponed to the date on which the FDA has completed assessments of at least eight such authorities.”

Regarding Germany, the Annex has a surprise too. Indeed, the German Federal States are responsible for GMP supervision. Although a coordinating body (ZLG) exists, the responsibility for GMP monitoring lies solely with the Federal States. Nevertheless, the Agreement provides that not the Federal inspectorates but the following authorities be assessed by the FDA:

  • Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) – Federal Institute for Drugs and Medical Devices
  • Paul-Ehrlich-Institut (PEI) – Federal Institute for Vaccines and Biomedicines
  • Bundesministerium für Gesundheit (BMG) – Federal Ministry of Health / Central Authority of the German Länder for Health Protection Regarding Medicinal Products
  • Bundesamt für Verbraucherschutz und Lebensmittelsicherheit (BVL) – Federal Office of Consumer Protection and Food Safety
  • Federal Ministry of Food and Agriculture


◆  USP Draft Chapters on Elastomeric Closures <381>, <382>, <1381> and <1382> (10-May-17 ECA)

The U.S. Pharmacopeial Convention (USP) proposes to revise and to develop the following general chapters:

  • <381> Elastomeric Closures for Injections (revision, proposed new title: Elastomeric Components used in Injectable Pharmaceutical Packaging/Delivery Systems),
  • <382> Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems (new),
  • <1381> Elastomeric Evaluation of Elastomeric Components Used in Pharmaceutical Packaging/Delivery Systems (new), and
  • <1382> Assessment of Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems (new).

The drafts of these four chapters have now been published for public comment in Pharmacopeial Forum (PF) 43(3) [May–Jun. 2017]. Deadline for comments is July 31, 2017.

Together with the above mentioned proposed change of the title, the USP Packaging and Distribution Expert Committee is proposing the following revisions which will update and expand the scope of the current chapter <381>:

  • Emphasize the baseline requirements for the selection of thermoset and thermoplastic elastomeric components;
  • Expand the scope to include all elastomeric components used in an injection packaging system. Elastomeric components include, but are not limited to, those used for vials, bottles, prefilled syringes (plungers, needle shields, and tip caps), cartridges (plungers and seal liners), injection ports for flexible bags and infusion sets, and plungers for single-use syringes;
  • Delete the Heavy Metals <231> testing and add a modern method for extractable element determination;
  • Omit functionality tests and assessment from the chapter and move them to the two proposed new chapters:

A) Functionality tests appear in Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems <382>. The proposed new general chapter will address the fitness-for-intended-use functionality requirements of elastomeric packaging/delivery systems that are intended for injectable dosage forms. When properly fitted with dimensionally compatible packaging/delivery systems, the closures are intended to protect and contain the drug product while enabling safe and effective in-use product access. The function being performed by any single elastomeric closure type is dependent on the packaging/delivery system and may cover more than one functional parameter.

B) Baseline information for the assessment is provided in Assessment of Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems <1382> to assist users in the functionality assessment of elastomeric closures as part of packaging/delivery systems intended for injectable dosage forms. Proper selection and design of functionality assessment studies is based on sound scientific principles that are consistent with

– the nature of the packaging system and packaged drug product;

– the clinical use of the packaged drug product; and

– the perceived safety risk associated with the packaging system and drug product.

According to the proposal, alternative testing strategies for functionality assessment may be appropriate in certain circumstances with proper justification. In chapter <1382>, a more complete discussion of fitness-for-intended-use testing, as compared to closure functionality assessment in early package development, is presented including guidance on test samples and their preparation, test sample population size, test procedures, test acceptance criteria (data interpretation), and test outcome reporting.

– Develop an additional informational chapter, Elastomeric Evaluation of Elastomeric Components Used in Pharmaceutical Packaging/Delivery Systems <1381>, to support the current chapter revision by:

– Describing elastomeric components and their materials of construction for use in pharmaceutical packaging systems,

– Providing a high-level introduction to elastomer chemistry, manufacturing technology, and the post processing of components,

– Explaining basic functional characteristics of components,

– Designating baseline requirements,

– Discussing identification testing.

Additionally, minor editorial changes have been made to update the chapter to current USP style.

Furthermore, a workshop, Modernization of USP Packaging Standards for Glass and Elastomeric Components, will take place June 19–20, 2017 at the USP Meetings Center in Rockville, Maryland, to discuss these four proposals.

USP also provided a briefing list in PF 43(3) which includes monographs and/or chapters that both reference the general chapter <381> under revision and require revision to keep references to the General Chapter accurate. USP says that “other monographs and/or chapters may also be listed, even where the reference to the General Chapter remains unchanged, as additional notice to stakeholders where there is believed to be potential for the change in the general chapter itself to affect pass-fail determinations for particular monograph articles”.

Following your registration on the Pharmacopeial Forum website you get access to the complete drafts of general chapters <381>, <382>, <1381> and <1382>.


◆  Brexit: U.K. will become ‘Third Country’ according to EU Statement (17-May-17 ECA)

The EU Commission and EMA made a clear statement that after 30 March 2019, the Unit Kingdom will become a ‘third country’.

In a common Notice to marketing authorisation holders of centrally authorised medicinal products for human and veterinary use, the Commission and the Agency get the point strait that “all Union primary and secondary law ceases to apply to the United Kingdom from 30 March 2019, 00:00h (CET). That means that the U.K. will “become a ‘third country'”.

What does this mean for marketing authorisation holders? In the document, important aspects are listed which will need to be considered:

  • EU law requires that marketing authorisation holders are established in the EU (or EEA). That means a pharmaceutical company will need a registered and licenced office or facility with licence in the EU/EEA.
  • Some activities like, for example, batch release and pharmacovigilance activities must be performed in the EU (or EEA). So QP and QPPV must be located in the EU/EEA.
  • Possible changes to the terms of the marketing authorisation “in order to ensure its continuous validity and exploitation” should be considered.


Please feel free to ask us if you have any questions.

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