Cross-contamination in pharmaceuticals is a significant risk to public health and the issue of shared facilities where potent drugs are made is hotly debated. Brendan Cuddy, head of manufacturing and quality compliance service at the European Medicines Agency, explains what recently revised GMP guidelines on the matter mean for the industry.

Even small traces of an anomalous pharmaceutical within a prescribed drug can have deadly consequences. Because of this, manufacturers of medicinal products for human or veterinary use must ensure that their facilities and equipment are designed and used within carefully defined specifications.

Production plants must be built in such a way as to minimise the potential for errors, and to be cleaned and maintained effectively in order to avoid cross-contamination. Premises and equipment critical to the quality of the medicinal product should be subjected to appropriate qualification and validation. However, it is not sufficient simply to rely on design and infrastructure. During operations, manufacturers should ensure that appropriate technical, or organisational, measures are established to avoid mix-ups.

When medicinal products are made, accidental cross-contamination can result from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms, from active substances, other starting materials and other medicinal products being processed, as well as from residues on equipment, and from operators’ clothing. As a result, certain classes of medicine must be manufactured in dedicated facilities.

Shared concern

Whether products should be manufactured in self-contained environments, or in shared facilities, has been a difficult question for member state inspectorates. Before 1 March 2015, chapters three and five of the EU GMP Guide recommended dedicated facilities for "certain products", including highly sensitive materials (penicillin, for example) and biological preparations using live pathogenic microorganisms. It then specified that, in exceptional circumstances, campaign working may be acceptable for certain product types including antibiotics, hormones, and cytotoxic and active drugs.

During initial discussions, the EU GMP Inspectors Working Group (IWG) found that arriving at common interpretations of this part of the guide was difficult, and foresaw this resulting in different standards being required by different authorities. This, in turn, could lead to a range of methods of production and therefore medicines of varying qualities.

In 2005, the IWG agreed to develop this part of the guide following a risk-based approach underpinned by GMP principles. Research and discussion continued over a number of years and, while progress was slow, a revision of chapters three and five was published by EMA in December 2009.

The GMP IWG considered developing a list of products for which dedicated facilities would be mandatory, however this approach would have been inconsistent with principles of quality risk management (QRM), so there was a move away from using product categories to a focus on a scientific methodology based on a toxicological evaluation of products being manufactured in shared facilities.

A number of toxicological tools were available, but there was no advice on how to carry out an appropriate review and evaluation of pharmacological and toxicological data, so the IWG sought the assistance of the Safety Working Party (SWP), and their veterinary counterparts at EMA.

The former developed ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’. This document proposed a procedure for determining health-based exposure limits for a residual active substance, based on the method for establishing the permitted daily exposure (PDE). PDE is the dose of a specific substance to which an individual might be exposed, every day, over the course of a lifetime, with no adverse effect.

One public consultation on the SWP Guideline was held concurrently with another on the revised version of chapters three and five of the EU GMP Guide between January and June 2013. A workshop was held with industry stakeholders in September 2013 to finalise the document.

The updated chapters were published in August 2014. The new emphasis is on the use of quality risk management principles and the toxicological assessment to identify, assess and control the risks for cross-contamination. Following the evaluation, and depending on the level of risk identified, it may be necessary to dedicate premises and equipment for manufacturing. Prevention of cross-contamination should then be achieved through measures that guarantee the appropriate design and operation of manufacturing facilities and equipment.

New deal

Under the new guidelines, dedicated facilities are required when a medicinal product presents a risk because the risk cannot be adequately controlled by operational and/or technical measures; scientific data from the toxicological evaluation does not support a controllable risk (allergenic potential from highly sensitising materials, such as beta lactams, for example); and relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method. Other scenarios requiring separate facilities are described in the ‘Dedicated to purity’ boxout.

For other medicinal products, the output from the QRM process should be used to determine the necessity for dedicating premises and equipment. The revised fifth chapter offers considerable detail on the types of technical and organisational measures to prevent cross-contamination. Measures include closed systems for processing and material/product transfer between equipment or parts of the facility; physical barrier systems, including isolator; and disposable technologies.

The revised chapters came into effect on 1 March 2015, and the SWP guideline for setting health based exposure limits will be enforceable from June. A phased implementation strategy will give manufacturers time to evaluate their products and facilities and to take any necessary measures to comply. Toxicological evaluation should be carried out for any medicinal product newly introduced into a shared manufacturing facility after 1 June.

For human and veterinary medicinal products already produced in shared manufacturing facilities, the assessment should be carried out before December for the former and before June 2016 for the latter where the drugs have been made in a facility only dealing in products for animals. It is important to note that, for medicinal products already produced in shared manufacturing facilities, the evaluation may be replaced by existing arrangements, if they are scientifically justified.

The guidelines will pose a challenge to manufacturers, many of which have only limited toxicological expertise. Evaluations may have to be prioritised: in such cases, rationales for prioritisation based on worst-case first principles should be available and discussed in advance with supervisory authorities.

Enforcement of the guidance is the responsibility of the GMP inspectorates who will need to gain experience in the application of toxicological tools. The guidance describes how limit can be calculated, but does not address how those limits can be applied to manufacturing environments.

The GMP inspector will have to determine if manufacturers have correctly assessed risks, and implemented appropriate technical and operational control measures that account for such factors such as partial dedication of premises/equipment; dust containment systems; closed system processing; gowning controls; and controls for campaign manufacturing.

Inspectors may need to seek specialist toxicological support within their agencies, and the availability of such support may be limited.

Driven by data

The revisions to chapters three and five, which incorporate a toxicological evaluation based on occupational exposure limits, provide a very strong scientific, data-driven framework, which will enable manufacturers to evaluate risks and make considered decisions that will underpin rational investment in manufacturing facilities or equipment.

The current EU GMP framework is flexible, and enables manufacturing to take advantage of current and future developments that will minimise cross-contamination. The guide permits the use of sophisticated technical measures to control and reduce the risks for cross-contamination such as continuous manufacturing; barrier systems; and single-use/disposable systems to control and reduce risk.

Marketing authorisation holders must take into account scientific and technical progress where manufacturing and control methods are concerned, and introduce any changes that may be required to enable medicines to be manufactured and checked by means of generally accepted methods. Manufacturers, in turn, should not feel discouraged from developing new concepts or technology to manufacture products and minimise cross-contamination, provided they have been validated to standards at least equivalent to those set out by the EU GMP.

Disclaimer: The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

Dedicated to purity

Under the new guidelines, scenarios that require separate facilities, or careful segregation, include:

  • handling live cells, and pathogenic organisms capable of persistence in the manufacturing environment (annexe two)
  • live biological agents used for manufacture of veterinary immunologicals (annexes two and five)
  • radiopharmaceuticals (annexe three)
  • poisons, such as pesticides (except where they are used for manufacture of medicinal products) and herbicides, should not be allowed in areas used for the manufacture and/or storage of medicinal products (chapter five)
  • manufacture of veterinary premixes (annexe four)
  • ectoparasiticides (annexe four)
  • manufacture of medicinal gases if taking place in a facility producing non-medicinal gases (annexe six)
  • plasma-derived medicinal products (annexe 14).

Ensuring compliance

Contamination control and steps taken to minimise the risk of cross-contamination should be seen by manufacturers as a series of successive linked events and measures. An appropriate control strategy would integrate all of these measures to ensure a more comprehensive approach is taken with respect to prevention and control to minimise the risk of cross-contamination. The development of such a strategy requires thorough process and facility knowledge. It should consider every aspect of cross-contamination control and prevention. Strategy elements should include:

  • design of plants and processes
  • control, including in-process systems
  • monitoring systems
  • raw materials
  • maintenance of equipment and facilities
  • process qualification
  • personnel
  • utilities
  • cleaning/sanitisation
  • investigations/CAPA/root cause determination.