Differences between the manufacture of APIs and medicinal products

by Rainer Gnibl

There are many parallels between the good manufacturing practice (GMP)- compliant manufacture of active pharmaceutical ingredients (APIs) and the production of medicinal products, as the comparison of EU Guidelines to GMP Part I for medicinal products and EU Guidelines to GMP Part II for APIs show. There are however also a number of important differences to be considered if manufacturers of APIs are to stay within the official requirements, thus ensuring GMP compliance.

As GMP inspector for the Government of Upper Bavaria and the EMA, Dr Rainer Gnibl (rainer.gnibl@reg-ob.bayern.de) is responsible for carrying out national and international inspections of manufacturers of medicinal products and active ingredients. He is Head of the national expert group EFG 02 GMP Inspections/GMP Guidelines, and lectures at the Friedrich-Alexander University in Erlangen-Nurnberg.

The goal of this article is not to compare, contrast or measure in detail the GMP requirements for the manufacture of APIs in accordance with the EU Guidelines to GMP Part II with those for the manufacture of medicinal products in accordance with the EU Guidelines to GMP Part I. It is rather to work out the essential differences or possible gaps for the area of APIs in contrast to the no doubt more familiar specifications for the area of medicinal products. The following remarks are guided by the structure of the EU Guidelines to GMP Part II.

Objective and scope

The first difference follows directly from the scope of application of the two GMP regulations. While the EU

Guidelines to GMP Part I is clearly fully applicable from the first step in the manufacture of medicinal products, the requirements for the applicability of the EU Guidelines to GMP Part II to the production of APIs are not always clear.

The question of the point at which the requirements of the EU Guidelines to GMP are applicable to the different process steps in the manufacture of APIs depends on the type of API or the manufacturing process. A detailed overview can be found in the introduction to the EU Guidelines to GMP Part II (see Figure 1).

The manufacture of sterile APIs constitutes a special case. The definition here is that the EU Guidelines to GMP Part II is only applicable until immediately before the sterilisation step, and that sterilisation or aseptic processing must then take place under the requirements of the EU Guidelines to GMP for medicinal products in conjunction with Annex 1. This is also consistently reflected in the scope of Annex 1.

Quality management Organisation and responsibility

The so-called quality unit as set out in Chapter 2.3 of the EU Guidelines to GMP Part II, which is independent of production, has an extended area of responsibility: it is also responsible for the quality control of the intermediates and APIs produced. This is particularly clear in Chapter 11.10 of the EU Guidelines to GMP Part II, which explicitly requires that the quality unit should have suitable laboratory facilities at its disposal. The division into the three areas of quality assurance, production and quality control traditional for medicinal products is therefore no longer applicable here. The only distinction made is between responsibilities of the quality unit and the responsibility for production activities (EU Guidelines to GMP Part II, Chapter 2.13). The responsibilities of the quality unit or units are described in detail in Chapter 2.3, and the responsibility for production activities in Chapter 2.4 of the EU Guidelines to GMP Part II.

Release to the market

The step of release to the market of APIs and intermediates must also be performed by the quality unit. In contrast to medicinal products, the release may not only be performed by qualified persons in accordance with EU

Type of ManufacturingApplication of this Guide to steps (shown in grey) used in ths type of manufacturing Chemical Production of Introduction of Production ofIsolation andPhysical Manufacturingthe API Startingthe API StartingIntermediate(s)purificationprocessing, MaterialMaterialinto processand packaging

API derived fromCollection of Cutting, mixing, Introduction of theIsolation andPhysical animal sourcesorgan, fluid, and/or initial API Starting Materialpurificaitonprocessing or tissueprocessingand packaging

API extracted fromCollection Cutting and Introduction of the Isolation andPhysical plant sourcesof plantinitial API Starting Materialpurificationprocessing, extraction(s)into processand packaging

Herbal extractsCollection

Cutting andFurtherPhysical used as APIof plantsinitialextractionprocessing extractionand packaging

API consisting ofCollection ofCutting/Physical comminuted orplants and/orcomminutingprocessing, or powdered herbscultivation and and packaging harvesting

Biotechnology:Establishment Maintenance Cell culture and/orIsolation andPhysical fermentation/of master cell of working fermentationpurificationprocesisng, cell culturebank and working cell bankand packaging cell bank

“Classical”Establishment Maintenance ofIntroduction of theIsolation andPhysical Fermentation toof cell bankthe cell bankcells into fermentationpurificationprocessing produce an API and packaging