Regulatory requirements for the sterile production of cytotoxic drugs

The sterile preparation of highly potent products of potentially hazardous substance demands particular responsibility, both for the product itself but also for the people who come into contact with it, to avoid the risk of possible contamination.

Major European Guidelines and Regulations

QuapoS 5:
Quality Standards for the Oncology Pharmacy Service.

Eudralex Volume 4:
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products November 2008 (rev.)

PIC/S Guide PE 010-4:
Guide to good practices for the preparation of medicinal products in healthcare establishments. March 2014.

Standards of Practice. Safe Handling of Cytotoxics.  Journal  of Oncology Pharmacy Practise, Vol.: 13 Suppl, 2007

Drug safety, patient and employee protection are at the core of the sterile production process and are the underlying reason behind sets of comprehensive and stringent rules and guidelines.

In order to meet these guidelines and fulfil those responsibilities, we must expect extensive demands to be set against the entire production process itself, the people involved in the process and upon quality control.

As we are focussing on the topic of the production of cytostatic agents in this brochure, we should also explore those requirements, if not already defined, as such factors essentially tailor both the structure and implementation of your production process. Whilst it is necessary to address the strict regulatory requirements that are to be met, the key lies in the ability to further identify guidelines that will contribute towards greater safety and protection in the sterile production process generally. That said, this is no easy subject, and not a topic we can cover comprehensively here. However, our aim is rather to provide orientation and support.

"The pharmaceutical company is responsible for its drugs and the information available for the use of these products. The particular properties of the active substances and the complex modalities of oncological therapy justify high expectations on the part of the users. User expectations often extend far beyond the legally stipulated minimum requirements. The requirements for drug manufacturers are therefore more demanding in the area of oncology than in the majority of the other drug groups." (Quote Quapo S51, 2013, chap. 3.1.1, p. 4)

Sterile production is subject, in most European countries, to increasingly stringent regulatory requirements. However, there are still no general rules, just guidelines and recommendations for the entire European Union.

As such, each sterile manufacturing company must ensure that they deal with the specific local legal and regulatory guidelines from the appropriate authorities within their own country, and be kept informed about respective mandatory measures.

In addition to this, it is also advisable to stay abreast of all the up-to-date and approved recommendations for contamination control. All of the above should not be considered an arduous task, but rather a guide towards safe and high quality sterile production.

For industrial enterprises, the handling of sterile pharmaceuticals throughout the EU, must adhere to the GMP Annex 12. Pharmacies however, are not considered to be ‘industrial enterprises’, so in this case, the GMP Guide is not necessarily a binding factor. In countries therefore, where cytostatic production takes place mainly within pharmacies, country-specific rules (e.g., Germany) or adherence to the general pharmaceutical work rules, as known as ‘Apothekenbetriebsordnung’ (ApBetrO3), or other European directives (e.g. PICS4, QuapoS51) apply. Fundamentally, the ‘ApBetrO’ rule applies with some of the lighter aspects of Annex 1. In which case, a production of A to C, rather than A to B, for example, would be sufficient.

Furthermore, you may also encounter special regulations, rules and policies for various additional aspects of sterile production, which may be either binding or simply recommended, or differ from country to country depending upon where the rules or regulations were issued, as is found with several EN, ISO or DIN standards (for example, DIN EN ISO 9001, DIN1280, EN 420, EN 388, EN 374, EN 14644, EN 14698, EN 12599, EN 12980), guidelines for personal protective equipment (e.g. 89/686/EEC), Hazardous Material Regulations (also known as ‘GefStoffV’), Technical Rules for Hazardous Substances (TRGS) and many others.

Regulations and guidelines are formed to deal with the all-important steps taken in the manufacture of sterile pharmaceuticals, and covers each and every aspect, from personnel, premises, equipment, and clothing, through to cleaning, sterilization, documentation, monitoring and quality control.

However, whether these are given as binding regulations or as recommendations, one consistent factor can be found in any publication; there are no regulations regarding the process of sterile production that give any clear lines of action, they simply provide a structure that must ultimately lead to a controlled and definitive result. How this is done is up to the experience of the manufacturing company.

So there is no specification, for example, on the cleaning agents or materials to be used, what cleansing frequency is necessary for which areas, no agreed frequency or content plan with regards to employee training, and the list goes on far beyond this. If you look at five different cytostatic/chemotherapeutic-producing companies, you will find five different cleanroom concepts.

The knowledge and experience of each manufacturing company therefore counts towards establishing both the basis of, and the compliancy with, suitable regulatory standards for the particular manufacturing company cleanroom concepts, which in turn leads to results meeting the quality criteria of regulations, but above all to a safe and effective product.

VWR is your qualified partner in this field. Our experts have the knowledge and experience to identify, together with you, the most efficient operating criteria for your business to create a sound and secure approach that protects people and products in the production process.


NOTE: All mentioned norms, regulations and other information may be subject to change.