Navigating Differences Between FDA and EMEA for Regulatory Compliance During Drug Development - A comparison of regulations and initiatives on both sides of the Atlantic reveals differences that inter

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Navigating Differences Between FDA and EMEA for Regulatory Compliance During Drug Development
A comparison of regulations and initiatives on both sides of the Atlantic reveals differences that international companies need to understand.


BioPharm International


Differences between EMEA and FDA Regulations

Given all these recent developments in the US and the EU, there are several disconnects in expectations between the FDA and the EMEA. These include differences in the coordination between GMPs and GCPs, guidelines governing investigational products, the role of Quality Assurance function, and the way amendments to CTAs and INDs are handled.

Coordination Between GMPs and GCPs

In Europe, GMPs and GCPs are much more closely associated and inter-related than in the US, where they are usually considered as two separate and independent regulations. One has only to examine section 5.14 of the ICH E6 Good Clinical Practice Guideline2 to see that the authors of this clinical guideline had an excellent appreciation for the ramifications of inadequate manufacturing or packaging on the clinical program. Scientists involved in the clinical supply chain can attest to the impact of clearly written directions for use on both subject compliance and clinical outcomes. Consider the likely actual dosing by subjects and clinical outcomes if directions were:
  • "Take two capsules daily."
  • "Take one capsule twice daily."
  • "Take one capsule in the morning and one capsule in the evening."
  • "Take one capsule every 12 hours with food."

Guidance documents for GMPs for Investigational Drug Products

In the EU, the general GMPs are found in 2003/94/EC, Laying down the Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational products for human use. 3 Greater detail (similar to the level of detail in 21 CFR 211) can be found in the Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practices for Medicinal products for human and veterinary use.10

A series of Annexes provide details on specific areas of activity; Annex 1, for example, covers the manufacture of sterile medicinal products. Annex 13, "Manufacture of investigational medicinal products [IMP]"4 provides 55 suggested approaches in 10 areas (e.g., personnel, premises, quality control, and documentation) that reflect the uniqueness of the clinical supply chain process. Annex 13 also addresses issues such as blinding, the use of comparator products, the use and security of randomization codes, label text, and extra QA controls needed due to the look-alike nature of blinded supplies, which have no equivalent or utility in commercial manufacturing and packaging operations.

In the US, the 1991 FDA Guidance Preparation of Investigational New Drug Products 11 identified a dozen areas where the implementation of traditional compliance approaches were difficult or impossible (e.g., process validation). For the most part, alternative approaches were not suggested or discussed. The principle of the January 2006 Draft Guidance INDs—Approaches for Complying with cGMP During Phase 1 8 was that the requirements of 21 CFR 211 need not be met for most investigational drugs. This statement precipitated substantial negative comments from the industry and the accompanying final rule was withdrawn (although the Guidance remains as a draft). The majority of the negative comments dealt with the risk to the public when these minimum GMPs would not be expected or followed. This guidance provided little in the way of specific alternative practices. In addition, there was no differentiation which and how items listed in the guidance differed from the GMPs described in 21 CFR 211.


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