New EU GMPs go into effect March 1st – Are you ready?

The European Medicines Agency’s new GMP requirements go into effect March 1st, 2015

The EMA’s new good manufacturing practice (GMP) requirements set forth in Chapters 3 and 5 in the EU GMP Guideline will go into effect March 1st, 2015. Pharmaceutical manufacturers of human medicinal products will be allowed 6-months to come into compliance with the requirements for new products being introduced into their facilities, and 1-year for existing products. Pharmaceutical manufacturers of veterinary products will have different timelines.

So, what are the changes? In Chapter 3, the most noteworthy change is to Section 3.6 which requires the prevention of cross-contamination by appropriate design and operation of manufacturing facilities. In addition, Section 3.6 states that dedicated facilities or equipment “when a medicinal product presents a risk because:

i.  the risk cannot be adequately controlled by operational and/or technical measures,

ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams) or

iii. relevant residue limits, derived from the toxicological evaluation, cannot be satisfactorily determined by a validated analytical method.”

While it’s easy to overthink the above requirements and begin believing that all high potency products will require dedicated facilities or equipment, that’s not the intent of the new requirements. The intent of the new requirements is to ensure that the potential for cross-contamination in a multi-product facility is managed in a manner appropriate to the “risk.” And, as most pharmaceutical professional know RISK = HAZARD X PROBABILITY. Furthermore, in order to appropriately determine the hazard, each medicinal product will require a toxicological evaluation that is based on scientific data. The purpose of this toxicological evaluation is to determine the health-based permissible daily exposure (PDE) limit for each pharmaceutical product.

Chapter 5, Sections 17 to 21 then continues to provide further guidance on prevention of cross-contamination and the toxicological assessment.

In order to support the above changes to the GMPs, in November of 2014, the EMA published a Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This guideline sets forth the approach for determining the Permitted Daily Exposure (PDE). Important statements in this guideline include:

  • The derivation of the PDE or Threshold of Toxicological Concern (TTC) should be the result of a structured scientific evaluation of all available pharmacological and toxicological data including both non-clinical and clinical data; and
  • The toxicological evaluation strategy and results needs to be thoroughly documented and needs to be an “expert” review (author’s note: it cannot be a poorly documented “cookie cutter” approach performed by amateurs).

While it is tempting to immediately focus your attention on the PDE equation in Section 4, it is important to thoroughly read and understand the entire guideline. For example, it should be noted that the use of the No-Observed-Adverse-Effect-Level (NOAEL) shown in the PDE equation may not always be the appropriate choice for the point-of-departure in the derivation of the PDE. NOAELs are typically derived based on animal data, short-duration studies, and are sometimes difficult to find a reliable value from a trustworthy source. The selection of other PODs may be more appropriate and this is where having a toxicology expert perform the evaluation can make a real difference.

Fortunately, for many generic pharmaceutical manufacturers, the toxicology experts at Affygility Solutions have prepared OEL Fastrac with ADE monographs for many common active pharmaceutical ingredients.  These monographs have been used by pharmaceutical companies throughout the world. To view our catalog of OEL/ADE monographs for purchase, please visit In addition to our OEL Fastrac monographs, the toxicology experts at Affygility Solutions can also determine OELs and PDEs for proprietary compounds. Please contact us for additional information.


About Dean Calhoun

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Dean is the President and CEO of Affygility Solutions. Affygility Solutions provides environmental, health and safety software, potent compound safety, industrial hygiene, containment validation services to the pharmaceutical, biotechnology, and medical device industry. "Dean's Google+ Profile"

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