Annex 1

Annex 12019-05-03T18:08:30+00:00

As the governing regulatory document of the European Medicines Agency (EMA), EU GMP Annex 1 discusses a full host of concepts related to manufacture of sterile medicinal products. In contrast to guidance documents issued by the FDA, EU GMP Annex 1 is interpreted as law, requiring strict adherence to the regulatory expectations contained, numerous of which allude to container closure integrity testing. In fact, current proposed and ongoing revisions increase the expectations of scrutiny on package integrity.

One key element from current and future versions of EU GMP Annex 1 is highlighted as a specific element of a pharmaceutical quality system:

“Processes associated with the finishing and transport of sterile products should not compromise the finished sterile product in terms of container integrity or pose a risk of contamination and ensure that medicinal products are stored and maintained in accordance with registered storage conditions.”

This statement, in essence, describes the need to ensure package integrity at major lifecycle stages: assembly and manufacturing, distribution, and shelf-life studies. Helium leak detection is frequently and successfully used to explore, develop, and validate assembly parameters, and studies can be developed to evaluate the impact of distribution and storage on integrity as well.

Section 8.18 of the current proposed revisions to Annex 1 states the following:

“8.18 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Form-Fill-Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject to 100% integrity testing. Samples of other containers should be checked for integrity utilising validated methods and in accordance with QRM, the frequency of testing should be based on the knowledge and experience of the container and closure systems being used. A statistically valid sampling plan should be utilized. It should be noted that visual inspection alone is not considered as an acceptable integrity test method.”

While the concept of 100% testing fusion sealed containers is not new in the EU or the US, language concerning the routine testing of other product-package systems is expanding. Helium is frequently implemented as a routine test. However, many choose to implement helium leak testing in their package development and manufacturing validation phases, gathering a strong, robust set of data to significantly reduce risk and be referenced as historical data and knowledge in a regulatory setting. By using a well-characterized package system, which has been demonstrated to have inherent integrity and a valid manufacturing process, less aggressive routine testing plans can be developed. Helium leak testing allows for a quality-by-design approach to package integrity, thus reducing the tendency to “test in” quality downstream.

With increasing focus on package-integrity related inquiries from regulatory bodies including the EMA, helium leak detection serves as the ideal baseline instrumentation for comprehensive package system evaluation across a company’s sterile product portfolio. The team at LDA can help design and implement container closure integrity testing plans to ensure compliance with these expanding regulatory expectations.