Breaking Quality News: Sterile Medicinal Products, Analytical Procedure Development, and Importation of Medicinal Products
September is a month of returning to the routine, but it is also an opportunity to start new and positive habits! Also, we know that the regulatory environment can be extremely challenging due to its constant changes and evolution, and it can be hard to be always up-to-date. So why don’t we take full advantage of this month to catch up on the latest changes in the Quality Landscape?
Our Knowledge Manager, àngel Buendía ?? , has compressed the key changes and brand-new regulations into this article so that you can make sure you’re staying right on track!
Curious about what these last months have brought us? Keep reading then!
After more than five years and two public drafts for comment, the European Union finally published the long-awaited changes to Annex 1, regulations part of the manufacturing of sterile drugs in the EU. Originally published in 2008, Annex 1 was recently revised in 2020.
According to the revised Annex 1:
“The GMP/GDP Inspectors Working Group and the PIC/S Committee jointly recommend that the current version of Annex 1, on the manufacture of sterile medicinal products, is revised to reflect changes in regulatory and manufacturing environments. The new guideline should clarify how manufacturers can take advantage of new possibilities deriving from the application of an enhanced process understanding by using innovative tools as described in the ICH Q9 and Q10 guidelines” (1).
What Are the Proposed Changes?
The main goals of this new version are to facilitate the implementation of ICH Q9 and Q10 principles as well as to expand and update the concepts, technologies, and processes previously not covered and clarify ambiguous areas.
It also details the Contamination Control Strategy, a new requirement. This document must define all critical points of the process, the controls carried out, their effectiveness, and the monitoring measures to control all the risks associated with product contamination, allowing manufacturers to assess the risk management process. Ultimately, the objective is to minimize the risk of microbiological contamination in sterile products.
Additionally, new concepts have been introduced in this version. Some principles mentioned in the regulation, such as Contamination Control Strategy, room qualification, classification, monitoring, and clothing can be used for other types of non-sterile products.
Furthermore, new sections are added (on the pharmaceutical quality system, water, steam, compressed gases, freeze-drying, FFS, closed and single-use systems, and a glossary) and more details are given on existing requirements (regarding sterilization, aseptic process simulation, continuous monitoring, sterilizing filtration, filter integrity, container integrity, extractables, and leachables).
How Will These Changes Impact Our Industry?
A full and comprehensive revision of Annex 1 was very much needed and loudly demanded by the pharmaceutical industry, since it has tremendously evolved during the last few years with the development of new technologies and many new products entering the market, such as personalized medicines.
Moreover, Regulatory Bodies have detected poor investigation practices, a lack of true root cause analysis, and inadequate identification of effectiveness during audits and inspections. Therefore, this review was crucial to strengthening the EU requirements and adapting the current regulatory system to advancing technologies.
Last but not least, this new version was used to reflect both insights and expectations in a cleanroom, equipment, and utility design as well the deployment of new rapid microbiological methods.
When Will These Changes Come Into Effect?
This new regulation will come into effect on August 25, 2023, exactly one year after the date of publication. However, 8.123 will be effective from August 25, 2024, two years after the publication.
Who Will Be Affected?
Manufacturers and producers of medicinal products for human use, veterinary use, and investigational medicinal products for human use, and arrangements for inspections supplementing Regulation (EU) on clinical trials.
DRAFT – not yet set for implementation.
Due to the harmonization process between the FDA and ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), guidelines Q14 (Analytical Procedure Development) and Q2 (R2; Validation of analytical Procedures) were published by the FDA on August 26, 2022.
Both guidelines – currently in draft status for public consultation – represent the harmonized scientific and technical principles for analytical methods throughout the lifecycle of analytical methods. They both describe the development and validation activities proposed during the lifecycle of an analytical method to assess the quality of medicinal products and medical devices (in combination products), using a risk-based approach for developing and methods validation.
What Are the Proposed Changes?
The new Guideline Q14 is intended to improve communication between industry and regulatory authorities.
The changes in Q2 (R2) provide a general framework for the validation of analytical methods. The traditional way of validation methods is now expanding with the use of new technologies, such as multivariate analytical procedures and real-time release testing (RTRT).
Traditionally, analytical development aims to develop a procedure that works. The method is validated without a thorough understanding of all factors that influence the method's performance. Once validated, the method remains unchanged until issues inevitably arise, and the method is modified and revalidated again. This traditional approach for method development and validation remains valid, but the novel approach provides more benefits. The main advantage is gaining a deeper insight into critical method characteristics. Additionally, there will be more regulatory flexibility when changes are necessary. The design of an analytical control space will permit the adjustment of some variables. A more thorough understanding of these critical parameters provides a more robust methodology.
The revised guide will also clarify common process validation features, such as NIR, nuclear magnetic resonance spectroscopy (NMR), and hyphenated techniques, for example, CE-MS, CE-ICP-MS, LC-NMR, GC-MS, and LC-MS.
How Will These Changes Impact Our Industry?
The application of science-based and risk-based principles will improve the efficiency and post-approval change of analytical methods. This will make it easier for manufacturers to change analytical methods for testing medicines post-approval. Overall, the guidelines promote more robust analytical processes.
These changes will provide timely access to new drugs for patients by eliminating multiple review cycles. Clear guidance in this area will encourage the use of more advanced analytical procedures and the modernization of existing methods, leading to more robust quality oversight by pharmaceutical drug manufacturers.
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When Will These Changes Come Into Effect?
The FDA is a founding regulatory member of ICH. By November 2022, the public comments will be reviewed and decisions will be taken for further revision directions. The goal of ICH is to finalize the guidelines by May 2023 (Step 4 adoption).
Who Will Be Affected?
It is important to note that the development of pharmacopeial analytical procedures is outside the scope of these guidelines.
Implementation: August 21, 2022
In February 2022, the European Commission published the new Annex 21 to the EU GMP guidelines. It came into force in August 2022 and is intended to summarize all existing EU GMP requirements for importing medicinal products from outside the EU and European Economic Area (EEA).
Annex 21 sheds light on the act of importation, answering frequently asked questions such as: Is a Qualified Person (QP) certification or confirmation necessary upon the importation? Is any additional paperwork needed for the QP before the imported product may be processed further? How should the product(s) be stored after importation? When can a QP certify a batch?
It aims to clarify the application of GMP principles in the importation of Medicinal Products and the sites which are considered to have specific responsibilities and required to have a Manufacturing Import Authorization. But what are the Annex 21 key issues that you should be aware of?
What Are the Proposed Changes?
Testing on Importation:
The main changes concern the inclusion of Investigational Medicinal Products (IMPs): Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products, that do not have a marketing authorization in the EU/EEA and are directly re-exported, are not included.
According to Annex 21, once a batch of a medicinal product has been physically imported into the EU/EEA, including clearance by customs, it is subject to QP certification or confirmation.
In particular, while performing the batch certification, a QP has to ensure that the medicinal product imported from a third country was manufactured in accordance with (as applicable):
The EU GMP Annex 21 does not change the fact that with respect to batch release all requirements already stated in the EU GMP Annex 16 should be fully considered.
What the EU GMP Annex 21 clarifies is that the site of the QP certification or QP confirmation of the batch is responsible for qualifying the third country manufacturer and should regularly monitor its performance by periodic on-site audits (performed themselves or outsourced to a third party).
GMP Requirements:
This new annex states that the manufacturing activities carried out in third countries prior to import, must be:
To ensure that the GMP level is up to standard, the manufacturer in the third country must be qualified by the site performing QP certification or QP confirmation and there must be regular on-site audits.
Documentation:
According to this Annex, full batch documentation must be available to the MIA holder responsible for QP certification or QP confirmation of the batch. This entity should also have access to the relevant ordering and delivery documentation, covering details such as:
Who Will Be Affected?
The new Annex lays out specific requirements, including a documented pharmaceutical quality system, product quality reviews, appropriate premises and equipment, documentation, and operational expectations, for these two sites:
1. Site of physical importation: Must at a minimum document the details of the transportation and receipt of the products, further details are given in Annex 16 of EU GMP.
2. Site of QP certification or QP confirmation: QP confirmation is applied to bulk or intermediate products.
Naturally, written agreements must be in place in accordance with Chapter 7 of the EU GMP Guide to outline the responsibilities and activities of each and every site.
How Will These Changes Impact Our Industry?
The Annex lays out the principles and guidelines applicable to a Manufacturing Import Authorization holder that imports medicinal products (human, investigational, and veterinary) crossing EU/EEA borders.
It also deepens the scope and responsibilities of the QP together with what is already specified in Annex 16, reinforcing the need for maintaining QP oversight of activities performed in the third county, ensuring EU GMP equivalence and MA compliance for manufacturers and exporters.
Now that you’re fully informed and up-to-date, it’s time to start working to become fully compliant!
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