20/21 April 2021
According to the provisions of guideline ICH Q7, GMP requirements must be met as soon as a starting material is first used in the active ingredient manufacturing process. The manufacture of the starting material itself is not within the scope of ICH Q7. The drug product manufacturer, who is ultimately responsible for the quality, safety and efficacy of his product, is still responsible, however, for proving that the starting material had also been produced in accordance with the base standards. That means that the manufacturer should at least have an effective quality assurance system. Authorities expect this evidence in the course of the approval procedure. Audits as a means of control and quality assurance are indispensable; but to which standards - if not to those of ICH Q7 - should manufacturers of starting materials be audited?
In order to close this gap, the APIC's 3rd Party Audit Task Force has developed a guideline by the name of "APIC Guide for auditing registered Starting Materials manufacturers" which has recently been published on the APIC website. This document is not only supposed to define audit standards; the introduction lists further reasons for the development of this guideline:
The guideline's structure generally follows that of the ICH Q7 guideline, although the chapters not applicable to starting materials (e.g. 17. "Agents, Brokers, Traders, Distributors, Repackers and Relabellers" and 19. "APIs for use in Clinical Trials") were left out. The names of the chapters and subsections have been altered accordingly (e.g. "Reprocessing and rework of materials" instead of "Rejection and reuse of materials" in ICH Q7), as were the subsections' topics. Chapter "Quality Management", for example, only contains "Principles" und "Internal Audits" as subchapters, without the "Responsibilities of the Quality Unit(s)", "Responsibility for Production Activities" und "Product Quality Review" from ICH Q7. Same as with API plants, the manufacturers of starting materials are expected to have an independent quality unit releasing or rejecting batches.
The following is a selection of other important GMP topics and requirements for starting material manufacturers:
Buildings and facilities
Defined areas should be available for the following activities:
Maintenance and cleaning of equipment
There must be written instructions for equipment cleaning. These should contain at least:
Computer systems should have sufficient control mechanisms to prevent unauthorised access to or altering of data.
The complete validation program as required for active pharmaceutical ingredients is not expected. The starting material manufacturer should, however, provide proof of the consistency and stability of his production processes, cleaning procedures, analytical methods, etc.
An interesting detail can be found in "12 Laboratory Controls" of the APIC guide. This chapter explicitly mentions "Elemental Impurities". The starting material manufacturer is expected to define specifications and acceptance criteria for this class of impurities, amongst others. Section 12.12 of the guideline says: "Appropriate specifications including acceptance criteria for impurities (e.g. residual solvents, elemental impurities, related substances) should be established for RSM consistent with the Starting Material manufacturing process." The APIC guide thereby acknowledges the provisions of guideline ICH Q3D.
The guideline is supplemented by an Aide Mémoire in the shape of a checklist - a useful document for the practical execution of audits.
This guide's scope includes starting materials for APIs to be used in human and veterinary drug products. Beside the chemically and synthetically produced starting materials, one chapter also covers the specific requirements for starting materials manufactured through fermentation processes (no biotechnological processes). Raw materials, chemicals, etc. are not covered; if a risk assessment showed them to be quality-critical, however, the principles of this guideline could be applied to this material or its manufacturer, as well.