A Review Of Recently Issued EMA Annexes & Their Impact On Manufacturers

By Peter H. Calcott, Ph.D., FRSC, president and CEO, Calcott Consulting LLC

The European Medicines Agency (EMA) is constantly adjusting its regulations, annexes, and guidances in responses to the needs of the industry, and the last 12 months have been no different. During this period they have issued a total of three revisions to established annexes and also issued a brand new guidance document in the GMP world. This article will focus on these four documents and describe what has changed and what it means to pharmaceutical companies.

Annex 15: Qualification and Validation

At the end of March 2015, EMA issued a revision to Annex 15: Qualification and Validation, to bring it into alignment with the previously issued Guidance on Process Validation. The deadline for implementation in all countries was October 2015. But based on my experience in the industry, I am sure there are still companies that have not yet implemented it.

The original document was first issued in 2001, so this revision has a totally new tone. The strategy of lifecycle management of product development and realization is well-described in the new annex. Thus, it indicates that process validation should first be contemplated in the development stage. In this stage, a strategy to demonstrate scale-up to commercial production should be built, along with development of tactics to assure continued operational quality through continuous verification. Thus, this annex should be considered with the ICH documents Q8-11.

This new annex describes the elements of process validation and also the qualification of facilities, equipment, utilities, and auxiliary processes such as shipping, methods, and cleaning. Now that agencies expect all legacy processes to be validated, the need for retrospective process validation is no longer valid. The annex describes the various elements that are required in a rugged validation and qualification program in a concurrent and prospective manner. This includes organization and planning, documentation including master plans, stages in the process, and requalification.

A major emphasis on quality risk management (ICH Q9) is made to justify the level of detail in the approaches to all aspects of validation. But perhaps the highlight is a section on the role of change control and how it ties into validation. This is important reading. This pivotal section describes the interplay between the design space and the management of change. Because this type of change within the design space will not result in a submission, it is critical that it is managed effectively internally.

In the area of stages of qualification, there is an emphasis on the early phase of design qualification as well as the precursor element of development of user requirements. This is, in my opinion, an area where we, as an industry, do not do a good job, except in the computer system arena.

A clear statement on the appropriateness and acceptability of using factory acceptance testing as a part of validation is made, stressing that the validity of using this approach rests with assuring that the transportation does not impact the testing conclusions.

Annex 16: Certification by a Qualified Person and Batch Release

October 2015 welcomed a revision to Annex 16: Certification by a Qualified Person and Batch Release. This document was effective as of April 2016, so I am confident that there some companies still haven’t implemented this document. This revision is designed to clarify the responsibilities of all parties in the release of medicinal products to both market and clinic. Ultimately, the license holder takes full responsibilities for the product, with certain responsibilities assigned to the qualified person (QP). Batch release comprises three elements:

1. Assuring that the manufacture and testing is in compliance with the defined procedures
2. Certification by the QP that the batch is in compliance with the license and the GMPs
3. Transfer to saleable stock is performed only after certification: If performed at a distance, the control and relationship must be defined in a technical agreement between parties.

Overall, this assures that the batch is only released if it meets the requirements of the authorization, is made by appropriate GMPs, and meets other legal requirements. If a deviation is noted, each QP involved must be aware of and confident in the impact of the deviation. In order to make a valid decision, the QP must be knowledgeable of the manufacture, testing, and operations and be confident that the operations are conducted appropriately. If the QP is at a distance, again, he may accept the conclusions of a fellow QP that is knowledgeable of the operations. If not, the QP can audit or accept the conclusions of an auditor with whom he is confident.

The details and requirements of certification are described for products made in the EU, as well as those manufactured outside the EU for use in the EU. When the QP certifies the acceptability of a product or intermediate, he is assuring that all previous activities related to the product are acceptable. In order to do that, the QP must have access to all relevant information that is pertinent to the product up to that stage of manufacture. The annex describes all the individual requirements for certification, and this represents an effective checklist for consideration in SOP development.

As supply chains take on more complex structure, sections describing “relying on third party assessments” are relevant reading. Of course, in real life operations, deviations occur and handling them effectively is critical. These should be codified in procedures, a topic that is described in detail. The release of a batch occurs only after certification, and measures to prevent premature release should be in place. For locations at a distance to the QP, agreements must be in place to describe mechanisms to meet the requirements outlined. Templates for acceptable certification by the QP are included for reference.

Annex 17: Real Time Release Testing

September 2015 marked the release of a new draft of Annex 17: Real Time Release Testing. The consultation period concluded in December 2015, and the new Annex became effective 6 months later. This rewrite is significant since it took a previous annex related to parametric release and expanded it to reflect real time release testing (RTRT). This marks the abandonment of conventional quality control end product testing.

Previously, parametric release only applied to terminally sterilized products and the terminal sterility test, but with the issuance and implementation of ICH Q8-11, this annex has been expanded. Regulators now recognize that good process control, monitoring, and process verification can assure that a product can be found acceptable without the need for final product testing. This document applies not only to terminally sterilized products, but to active pharmaceutical ingredients and intermediates as well.

For this approach to be implemented by a manufacturer, it must receive prior approved by the relevant competent authorities. To gain that approval, the following criteria must be made:

1. Real time measurement and control of relevant in-process material attributes and process parameters should be accurate predictors of the corresponding finished product attributes.
2. The valid combination of relevant assessed material attributes and process controls as the surrogates of finished product attributes should be established with scientific evidence founded on material, product, and process knowledge.
3. The combined process measurements (process parameters and material attributes) and any other test data generated/gathered during the manufacturing process should provide a robust foundation for RTRT and batch disposition decision.

To meet these criteria, the annex defines a comprehensive set of requirements. However, it also points out that if the control strategy requirement is not met, then the product may not be release by final product testing.

A section on parametric release describes the requirement for terminally sterilized products, and I suspect that products made by aseptic processing may not be released using the strategy outlined here in the sterility assurance arena. For non-sterility assurance tests, real time release may be petitioned with the appropriate control strategy and data to support the decision.

Guideline on Process Validation for the Manufacture of Biotechnology-Derived Active Substances

In April 2016, the Committee for Medicinal Products for Human Use (CHMP) released the guidance document Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission, which goes into effect November 2016.

This guidance applies to active pharmaceutical ingredients of biotechnology derived materials and allows either the modern or traditional approaches to validation described in Annex 15 to be used. Process verification can be implemented irrespective of how the product was developed. They recognize that process knowledge can be gained in modern development or later in operations if more traditional approaches are used.

The modern approach using life cycle management in process development, validation, and verification is described and is compatible with the strategy in Annex 15. This knowledge should be included in submission for licensure but needs to be continued in the commercial phase to confirm the predictions of development and validation.

A Points to Consider section describes a number of scenarios providing real life examples for the reader. These include evaluation and verification of upstream processes, use of single use materials, and multiple harvests. Sections on downstream processes include evaluation, verification, reprocessing, hold time, storage, and transportation. The challenges of plant expansions including new facilities are also discussed.

In all these documents, as is customary in the EU, there are comprehensive glossaries of terms, which serve to clarify the meaning of the body of the texts.

About the Author

Peter H. Calcott, Ph.D., is president and CEO of Calcott Consulting LLC, which is focused on delivering solutions to pharmaceutical and biotechnology companies in the areas of corporate strategy, supply chain, quality, clinical development, regulatory affairs, corporate compliance, and enterprise e-solutions. He is also an academic program developer for the University of California, Berkeley in biotechnology and pharmaceutics postgraduate programs. Previously, he was executive VP at PDL BioPharma, where he was responsible for development and implementation of quality and compliance strategy across the corporation. He has held numerous positions in quality and compliance, research and development, regulatory affairs, process development and manufacturing at pharmaceutical companies including Chiron, Immunex, SmithKline Beecham, and Bayer. He has successfully licensed products in the biologics, drugs, and device sectors on all six continents. Dr. Calcott holds a doctorate in microbial physiology and biochemistry from the University of Sussex in England.