GMP Compliance Adviser Update No. 3/2017

With this GMP Compliance Adviser UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

GMP in Practice

6.E Installation Qualification (IQ)

Batch Release

GMP Regulations

D.1.5 21 CFR Part 4 Regulation of Combination Products
D.25 Guidance for Industry and FDA Staff:
Current Good Manufacturing Practice Requirements for Combination Products

GMP in Practice

Chapter 6 Qualification

6.E Installation Qualification (IQ)

During an Installation Qualification (IQ) the equipment is checked to conform to the requirements placed in the Design Qualification (DQ) requirement specifications and to show/demonstrate that the installation has been performed correctly. The minimum requirements for testing are given in Annex 15 of the EU GMP Guidelines. Special attention within this qualification phase is placed on the technical documentation, the scope of which is to be precisely defined as part of the DQ. The technical documentation is to be provided by the equipment supplier and must reflect the as-built status after acceptance testing. IQ is performed after delivery in parallel to the installation at the customer’s proscribed site. Depending on the type of equipment, a FAT (factory acceptance test at supplier site) can be performed, during which parts of the IQ tests may be executed. The SAT (site acceptance test at customer site) is also typically performed before the IQ. The chronological order of the equipment commissioning and its IQ depends upon the project framework and the type of equipment. The IQ documentation comprises the plan, protocols and report as well as the technical documentation included. Once the IQ has been completed and the status of the equipment has been defined, a change control system must be implemented, since changes from this point onward have an influence on its qualification status. For this purpose, agreements between customer and suppliers are to be made. (Thomas Peither, Ulrike Reuter, Rainer Röcker)

Chapter 14 Laboratory Controls

14.J Batch Release

The revised version of Annex 16 regulates the batch release of medicinal products, especially the activities that the certifying Qualified Person is responsible for, in much greater detail than the previous version. The process is divided into three separate process steps:

  • verification of certification requirements
  • batch certification and
  • batch release as a change of status.

The activities that the certifying Qualified Person has to carry out personally and those that can be delegated are also clearly outlined. Certain QA elements play an important part and should receive special attention from the Qualified Person. The reliability of these PQS elements is essential for the certifying Qualified Person. No changes were made in the latest version in relation to the acceptance of confirmations from other Qualified Persons (certificate of conformance, CoC) in cases of partial manufacture in the EU. The Qualified Person can still rely on the certificate of conformance of another Qualified Person during batch certification. In the case of imported products, this type of confirmation (CoC) by persons from a third country regardless of their qualification is not permitted. The certifying Qualified Person for imports has overall responsibility for all manufacturing activities carried out in third countries. The mandatory EU reanalysis of imported products remains in place. However, it was expanded to allow the option of carrying out sampling in a third country (under certain conditions). The global product and process flow is a major challenge for the certifying Qualified Person. The requirements (certification requirements) that must be fulfilled before batch certification now take globalisation into account and are presented in the revised Annex 16 in greater detail than previously. Both GMP compliance and GDP compliance are important in order to meet the requirements implemented as a result of the "falsified medicines directive" with a view to ensuring an unbroken supply chain for active substances and medicinal products. It is now clearly specified that a certification of medicinal product batches with OOS results that deviate from the specification filed in the authorisation dossier for active substances, excipients and finished medicinal product is not permitted. (Rainer Gnibl, PhD)

GMP Regulations

Chapter D

D.1.5 21 CFR Part 4 Regulation of Combination Products

A new Subpart B – Postmarketing Safety Reporting for Combination Products was added to 21 CFR Part 4. It identifies postmarketing safety reporting requirements for combination product applicants and constituent part applicants.

Subpart B does not apply to investigational combination products, combination products that have not received marketing authorization, or to persons other than combination product applicants and constituent part applicants. It should be regarded supplementary and does not supersede other provisions of Chapter I: Food and Drug Administration.

D.25 Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products

The US Food and Drug Administration released a 59-page final guidance on the CGMP requirements for combination products. The guidance describes and explains specific provisions from 21 CFR Part 4 (final rule on CGMP for combination products) that was originally released in 2013. A draft version of this document was issued in January 2015.

21 CFR Part 4 did not establish any new requirements but clarified which CGMP requirements apply when drugs, devices and biological products are combined to create combination products.

This final guidance to 21 CFR Part 4

  • applies to all combination products
  • provides a definition of “combination product” according to FDA
  • gives an overview of 21 CFR Part 4
  • describes the role of the lead center and other Agency centers (e.g. CDER, CBER, CDRH)
  • addresses certain general considerations for CGMP compliance for combination products
  • presents the purpose and content of specific CGMP requirements addressed in 21 CFR Part 4
  • analyses hypothetical scenarios that illustrate how to comply with certain requirements for specific types of combination products (for a prefilled syringe, drug-eluting stent and drug-coated mesh)
  • refers to a “CGMP operating system” meaning the operating system within an establishment designed and implemented to address and meet the CGMP requirements for manufacturing a combination product
  • clarifies how to deal with constituent parts of cross-labelled combination products
  • explains the two ways to demonstrate compliance
    - by either a streamlined approach or
    - a CGMP/QS approach
  • addresses the documentation needed for a CGMP approach.