Replacing a QP: what Art. 48, Section 20 AMG and Annex 16 require of the authorization holder

When the only named Qualified Person resigns, falls ill or retires, the holder of a manufacturing authorization faces the same question in three places: who may certify batches now, what has to be notified to the authority, and who may deputize in the meantime? The answers are spread across Directive 2001/83/EC, the German Medicinal Products Act (AMG), the German manufacturing ordinance (AMWHV) and Annex 16 of the EU GMP Guide. This article orders them by the situation in which they are needed and names, for each, the place where it is written.

A QP vacancy is a license problem

Art. 48(1) of Directive 2001/83/EC requires Member States to ensure that the holder of the manufacturing authorization "has permanently and continuously at his disposal the services of at least one qualified person, in accordance with the conditions laid down in Article 49, responsible in particular for carrying out the duties specified in Article 51". If the holder personally fulfills the conditions of Art. 49, he may himself assume the responsibility (paragraph 2). "Permanently and continuously" is the reason a vacancy becomes a problem before the next batch is waiting for release.

German law draws the consequence at the level of the license. Under Section 14(1) no. 1 AMG, the manufacturing authorization may be refused if there is not at least one person with the expertise required under Section 15 (the qualified person under Section 14) who is responsible for the activity named in Section 19; under no. 4, if the qualified person cannot permanently fulfill the obligations incumbent on her. The qualified person is therefore part of the license, not a notification beside it. And Section 13(1) sentence 3 AMG makes clear that the licensing requirement applies correspondingly to a test on the basis of which the release of the medicinal product for placing on the market is declared: release testing is manufacturing that requires a license.

The notification is in Section 20 AMG

The duty to notify the authority of the change falls on the authorization holder, not on the person. Section 20 AMG: the holder of the license has to notify the competent authority in advance, with supporting evidence, of any change to one of the particulars named in Section 14(1); in the event of an unforeseen change of the qualified person under Section 14, the notification has to be made without delay. The default is therefore notification before the change; only an unforeseen change allows notification without delay afterwards. The root in Union law is Art. 46(c) of the Directive: the holder has "to give prior notice to the competent authority of any changes he may wish to make to any of the particulars supplied pursuant to Article 41; the competent authority shall, in any event, be immediately informed if the qualified person referred to in Article 48 is replaced unexpectedly".

In practice this notification is frequently attributed to Section 16 AMWHV. It is not there. Section 16 AMWHV is titled "Release for placing on the market" and governs the conditions under which the qualified person may release a batch: only in accordance with instructions drawn up beforehand and only if she is familiar with the product and with the procedures used for its manufacture and testing (paragraph 1), and only if four conditions are met (paragraph 2): the manufacturing and test records are signed, essential information such as the manufacturing conditions and the results of in-process controls has been taken into account, the documentation review confirms conformity with the specifications including the final packaging, and conformity with the marketing authorization documents is established. The section does not contain a word about notifying an authority.

Who may be a QP

Art. 49(2) of the Directive requires a diploma awarded on completion of a university course "extending over a period of at least four years" in one of six scientific disciplines: "pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology". Three and a half years suffice where the course is followed by a year of theoretical and practical training including at least six months in a pharmacy open to the public. The course has to cover twelve basic subjects, from experimental physics to pharmacognosy. Paragraph 3 adds "practical experience over at least two years, in one or more undertakings which are authorized to manufacture medicinal products, in the activities of qualitative analysis of medicinal products, of quantitative analysis of active substances and of the testing and checking necessary to ensure the quality of medicinal products", that is in quality control; the period is reduced by one year for a five-year course and by a year and a half for a six-year course.

Section 15(1) AMG implements this: expertise is evidenced by licensure as a pharmacist, or by a certificate of a university degree of at least four years in pharmacy, chemistry, pharmaceutical chemistry and technology, biology, human or veterinary medicine, together with at least two years of practical activity in qualitative and quantitative analysis and other quality testing of medicinal products. For blood products, sera, vaccines, advanced therapy medicinal products, radiopharmaceuticals and active substances, paragraphs 3 and 3a set subject-specific rules: the practical activity in analysis is replaced by activity in the relevant field, two or three years depending on the type of product, for instance three years in medical serology or microbiology for sera, vaccines and allergens (paragraph 3 sentence 2) and three years for radiopharmaceuticals (paragraph 3a no. 5), but two years for gene therapy medicinal products, somatic cell therapy medicinal products and active substances (paragraph 3a nos. 1, 2 and 6). Under paragraph 4, the practical activity has to be completed in an undertaking holding a manufacturing authorization of an EU or EEA state or of a state with a mutual recognition agreement. And under paragraph 6, an activity as qualified person examined by one authority also qualifies within the area of responsibility of another authority, unless there are substantiated indications that the previous expertise is insufficient for the new activity.

What the QP owes per batch

Art. 51(1) describes the duty with a subordinate clause that makes the external QP possible in the first place: the qualified person, "without prejudice to his relationship with the holder of the manufacturing authorization", is responsible for securing that, for medicinal products manufactured within the Member State, "each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that Member State and in accordance with the requirements of the marketing authorization" (point (a)), and that, for medicinal products coming from third countries, "each production batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary" (point (b)). She ensures that the safety features under Art. 54(o) have been affixed. Under paragraph 3, she certifies this "in a register or equivalent document provided for that purpose", kept up to date as operations are carried out and kept at the disposal of the authority for at least five years. Section 19 AMG is the German version: the qualified person is responsible for ensuring that each batch of the medicinal product has been manufactured and tested in accordance with the provisions on trade in medicinal products, and certifies this for each batch in a continuous register or comparable document before it is placed on the market.

Annex 16, in its current version of October 2015 and in operation since April 15, 2016, fills this duty in. Its General principles place the responsibility on two shoulders: "The ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, quality and efficacy, lies with the marketing authorisation holder (MAH). However, the QP is responsible for ensuring that each individual batch has been manufactured and checked in compliance with laws in force in the Member State where certification takes place, in accordance with the requirements of the marketing authorisation (MA) and with Good Manufacturing Practice (GMP)." Batch release then has three steps: the checking of manufacture and testing, certification by the QP as "the quality release of the batch", and the transfer to saleable stock, which, where another site is involved, is governed "in a written agreement between the sites".

Section 1.1 sets out who may certify: "Each batch of finished product must be certified by a QP within the EU before being released for sale or supply in the EU or for export. Certification can only be performed by a QP of the manufacturer and/or importer which are described in the MA." An external QP therefore has to be assigned to a manufacturer or importer named in the marketing authorization. Section 1.2 requires "detailed knowledge of the steps for which they are taking responsibility" and demonstrable continuous training on the product type, the processes, technical progress and changes to GMP; a QP who certifies without induction into the pharmaceutical quality system misses this section. Under section 1.4, for manufacturing steps performed at sites in the EU, "each manufacturing site must have at least one QP"; in the case of partial manufacture, the QP of the respective site confirms its steps (1.4.1), and the sharing of responsibilities "must be defined in a document formally agreed by all parties", including the responsibility for assessing deviations (1.4.3).

Section 1.6 names three things the QP must "personally ensure": that certification is "permitted under the terms of the MIA", that additional national requirements are met, and that certification is "recorded in a register or equivalent document". Section 1.7 lists 21 further points (1.7.1 to 1.7.21) that "may be delegated to appropriately trained personnel or third parties", where "the QP will need to rely on the pharmaceutical quality system and the QP should have on-going assurance that this reliance is well founded". Among them: the documented entire supply chain (1.7.2), available audit reports (1.7.3), "All manufacturing and testing processes remain in the validated state" (1.7.12), completed OOS and OOT investigations (1.7.16), technical agreements (1.7.18), self-inspection (1.7.19) and the safety features (1.7.21). Until a batch is certified, it remains at the site of manufacture or is shipped under quarantine to another site approved for that purpose (4.1), with physical or electronic safeguards against the transfer of uncertified batches (4.2).

Deputies, deviations and batches from third countries

Section 16(6) AMWHV draws deputizing narrowly: in cases of short-term unavailability, in particular through illness or leave, only by persons who possess the expertise under Section 15 AMG. A deputy without that expertise is thereby ruled out. In multi-stage manufacture, the qualified person may under paragraph 4 draw on confirmations given by other qualified persons within a quality system she recognizes, but remains personally responsible for the release of the batch as a whole. The license holder has to enable the qualified person to carry out her task and in particular to place all necessary means at her disposal (paragraph 7).

Certifying despite a deviation is possible under Annex 16 section 3, but under conditions: "Provided registered specifications … are met, a QP may consider confirming compliance or certifying a batch where an unexpected deviation concerning the manufacturing process and/or the analytical control methods from details contained within the MA and/or GMP has occurred. The deviation should be thoroughly investigated and the root cause corrected", where applicable with a variation to the marketing authorization; the assessment runs through quality risk management with the conclusion "that the impact is negligible" and considers inclusion in the stability program (3.1). Certification with open deviations and without a documented assessment is therefore not covered; it is covered only where registered specifications are met, after investigation and root cause correction.

For batches from third countries, the testing duty of Art. 51(1)(b) comes on top; Annex 16 section 1.5.4 repeats it: "Unless an MRA or similar agreement is in place between the EU and the exporting country, the QP is also responsible for ensuring that the finished medicinal product batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary". Sampling in the third country is permitted only with a documented risk-based justification, an audit, a comparative study and periodic re-analysis after import (1.5.5, 1.5.6). Art. 51(2) allows the exemption where arrangements with the exporting country ensure at least equivalent GMP standards and the performance of the controls there. In German law, Section 17(1) AMWHV requires that the testing under Section 14 has been carried out within the scope of the AMG, with two exceptions: for products brought in from the EU or EEA, where the testing was carried out there under the law applicable there and the control reports signed by the qualified person are attached (paragraph 2), and for imports from third countries where the conditions of Section 72a(1) sentence 1 no. 1 AMG are met or the testing has already been carried out in another EU Member State and the corresponding control reports have been transmitted (paragraph 3). That the third-country manufacturer demonstrably produces to standards at least equivalent to the GMP standards laid down by the European Union is something the qualified person has to satisfy herself of under Section 16(5) AMWHV, which ties in with multi-stage or outsourced manufacture under paragraph 4, by personal inspection or by confirmation from other sufficiently expert and suitable persons.

What follows for practice

For an authorization holder whose QP is leaving, the texts yield a sequence. First the notification under Section 20 AMG, as a rule before the change, with the evidence under Section 15 AMG for the successor. Then the deputy for the transition, who under Section 16(6) AMWHV may only be a person with the expertise under Section 15 AMG. For an external QP: her assignment to the manufacturer or importer named in the marketing authorization (Annex 16 section 1.1), a formally agreed sharing of responsibilities where several QPs are involved (1.4.3), a documented induction into product, processes and quality system (1.2), and the provision of all necessary means by the license holder (Section 16(7) AMWHV). For imported products: the testing under Art. 51(1)(b) and Section 17 AMWHV, unless an exemption under Art. 51(2) or Section 72a AMG applies. And for every batch: the certification in the register under Section 19 AMG and Annex 16 section 1.10, available for at least five years.

Directive (EU) 2017/1572 supplements Directive 2001/83/EC as regards the principles and guidelines of good manufacturing practice for medicinal products for human use and has replaced Directive 2003/94/EC; the duties of the qualified person remain in Art. 48 to 52 of Directive 2001/83/EC itself.

Entourage provides external Qualified Persons for batch certification, import testing and bridging a vacancy in QP on Demand, and arranges the staffing of an unfilled regulated function with a written agreement in Interim & Functional Sourcing.