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Although Annex 1 for the manufacture of sterile medicinal products has been changed several times in the last decades its fundamental structure remained unchanged over all these years.

The draft of Annex 1 and its consequences for the pharma production and technology also significantly determined the discussions of the more than 60 speakers from the pharmaceutical industry and from authorities and the 1.000 participants who convened at this year's Pharma Congress end of April in Düsseldorf again to discuss the latest GMP/FDA trends.

As Co-Chair of the working group on the Annex 1 revision, Dr Beate Reutter from the Landesamt für soziale Dienste in Kiel explained the reasons for the revision and why the draft also received a complete new structure:

  • Missing glossary
  • Missing integration of new technological developments
  • Lack of precision
  • Missing risk based approach to handle critical situations

Another aspect was to adapt the EU Guidelines to Good Manufacturing Practice to the ICH (International Council for Harmonisation) documents Q 9 (Quality Risk Management) and Q 10 (Pharmaceutical Quality System). Because so far they had not been reflected in Annex 1.

A first position paper was presented by the Annex 1 IWG Working Group (Inspectors Working Group) in 2014. The first draft followed in February 2016 and was published for public comments in December 2017.

Visual Inspection of Parenterals - Live Online Conference


5/6 October 2022

Visual Inspection of Parenterals - Live Online Conference

One focal point of the revised version of Annex 1 is the explicit inclusion of quality risk management and in this connection the expectation of a contamination control strategy as holistic approach. Dr Reutter explained both aspects at length when discussing the topics premises / equipment and media fills. As concern premises / equipment many requirements have been adopted from the previous Annex 1. The integration of quality risk management is new, such as

  • the definition of the appropriate clean room design for each process
  • the evaluation of the movement of material and personnel in the light of contamination and cross-contamination
  • the periodic requalification and requalification after changes of equipment, facilities or processes based on the principles of QRM (but for grade A and B zones, the maximum time interval for requalification remains 6 months and for grades C and D zones, the maximum time interval remains 12 months)

Comparable to the expectations of the American FDA the draft of Annex 1 also generally shows an increased focus on barrier systems and automation.

8.9. Where possible, the use of equipment, such as RABS (Restricted Access Barrier System), isolators or closed systems, should be considered in order to reduce the need for interventions into the grade A environment and minimize the risk of contamination Automation of processes should also be considered to remove the risk of contamination by intervention (e.g. dry heat tunnel, automated lyophilizer loading, SIP)

Therefore, in automated processes in the isolator it is possible to use a lower level of contamination control strategy. But carrying out the classical manual work under the laminar flow the contamination risk is significantly higher. Accordingly, the contamination control strategy has to be considerably more comprehensive.

Barrier Systems & Annex 1

Dr Daniel Müller, from the German local authority in Tübingen compared the new requirements for barrier systems with the previous requirements of Annex 1. Priorities are:

  • The entry of materials into the barrier system should be assessed and controlled.
  • The justification for turbulent air flow should be given in closed isolators.
  • The contamination control strategy should be based on a risk assessment and include the disinfection regime.
  • The background of the isolator should be chosen based on a risk assessment.
  • Automated processes reduce the number of interventions and should be preferred.

The ECA Foundation had set up a task force for commenting the draft of Annex 1. Dr Friedrich Haefele, Boehringer Ingelheim Pharma, summarised their assessments and comments concerning the topic barrier systems. In doing this he also compared the new requirements with the FDA Aseptic Guide and with actual industry guides. His assessment:

  • The guidance lacks homogeneity (in the wording) which might lead to confusion and misinterpretation.
  • The terms "disinfection, sterilisation, decontamination, sanitisation, biodecontamination" need an unequivocal definition, which should be used throughout the document in a uniform way.
  • The document focuses on the application of the quality risk management principles. But some sections contain specific and detailed requirements which often lack scientific prove and aren't always applicable especially for barrier technology processes.
  • Some requirements in chapters 5 (Premises), 6 (Equipment), 8 (Production and Specific Technologies) and 9 (Viable and non-viable environment and process monitoring) are applicable only for conventional cleanrooms (A/B classification).
  • Annex 1 should reflect the unique aspects of innovative barrier technologies as concerns minimizing the risk of contamination more clearly.

Continuous Manufacturing

Continuous pharmaceutical production has been an established topic already since the Pharma Congress 2012. This year was the first time that an EMA representative talked about the expectations of European authorities. According to Dr Nick Lee, Head of Department of Continuous Manufacturing at the Irish Health Products Regulatory Authority, HPRA, and member of EMA's Pat Team, continuous manufacturing is much more focussed on data than batch production. The continuous data monitoring alone produces huge amounts of data. In his opinion this monitoring is extremely important as well as understanding the strategy behind the continuous process. The documents submitted must be clear and comprehensible. "We want to understand you", said Dr Lee. He reminded the audience to think at the assessor when writing the documents to be submitted because he has to read and to understand the documents. Dr Lee urged the participants to refrain from the use of inhouse terms.

He considers the following elements to be key for continuous manufacturing: residence time distribution (RTD), and associated with this stability of materials which might remain in the manufacturing equipment for a much longer time than in the case of batch production. A number of guidelines which are already available provide some assistance even though no specific documents exist so far. In this context he mentioned the ICH series (ICH Q8, Q9 and Q10). ICH Q7 can be helpful as concerns the definition of the term "batch". Dr Lee added that the topics validation or validation of a continuous process are already described and referred to EMA's existing document on process validation. Possible approaches are the traditional approach to validation, the continuous one [Continuous process verification] or a hybrid of both. This is the same as concerns batch processes.

Dr Eric Meier, Head QA Continuous Manufacturing, Novartis, addressed quality aspects of continuous manufacturing. His vision is a continuous production - from the raw materials to the (non isolated) active pharmaceutical ingredients and to the final product. He also says that it is no problem that there are no specific rules concerning continuous manufacturing. And he also referred to the existing guidelines. Furthermore, the much discussed batch definition is broadly covered, according to Dr Meier. The batch size increases on the way from development to routine commercial production. And the more you learn the more the risk for the product decreases.

"Continuous" without PAT does not seem to be reasonable, according to Dr Meier. And then real time release is within reach, he added. For the use of PAT methods it should be taken into consideration, however, that their validation requires validated reference methods. In most cases these must, in turn, still be developed and validated before they can be used. It is also important to measure the material traceability. This is the time it takes until the active pharmaceutical ingredient ends up in the tablet. When asked "How long is continuous?", Dr Meier answered: "Days to months." And added: "Otherwise it does not make sense." The definition of minimum sampling and frequency of measurement was also interesting. He deduced it from the measurement of a quality parameter in terms of time or from the time the signal needs for instance from the lower alarm limit to the lower specification limit. The safety buffer after the signal has reached again the "green" area and it is once more possible to take usable material is defined as the double length of the minimum frequency of measurement.

Dr Giustino Di Pretoro, Janssen Pharmaceutica, presented the practical application. The company Janssen has committed itself to continuous manufacturing and has already two authorised lines or products from continuous manufacturing in Puerto Rico and Italy. According to Dr Di Pretoro quality is the main driver for the development of and switch to "continuous". "Until now 10 out of 265,000 tablets of a batch were checked during the quality control. Now we see them all."

According to Dr Giustino Di Pretoro the material properties are the central point. They play a much bigger role for continuous processes than in the case of batch production. Two parameters are especially important for the manufacture of tablets: flowability and compressibility. The lines can't work magic, said Di Pretoro. The variability of excipients also plays a much bigger role. That's why the company Janssen carries out "API Engineering" in order to make the active pharmaceutical ingredients usable for continuous processes. This requires many studies. Di Pretoro mentioned the study (DoE) to identify the connection between tablet relaxation and defects during film coating. But for one product it was not possible to find a connection. This is also possible.

Another important topic, also mentioned by Dr Lee, is the control strategy of the continuous process. To the authorities, for example, a controlled failure of the process was presented and the return of the system to a controlled condition. The OOS material produced during the failure of the system was rejected and the authorities took a positive view of the system.

But according to Dr Di Pretoro continuous manufacturing also has drawbacks. The change over time takes much longer than in batch processes. But they are reduced with an increasing experience of the process. "Lean projects" which simplify the operator's life are important, added Di Pretoro. At the beginning the yields can also pose a problem. In the case of Janssen software errors of the continuous lines had to be solved. In some cases the initial yield was only 50% of the current yield. Nevertheless, the possible savings are enormous if one considers scale-up and the fact that the process transfer from development to a bigger scale is not required, concluded Dr Giustino Di Pretoro.

Product Transfer - Live Online Training


18/19 October 2022

Product Transfer - Live Online Training

Track & Trace

According to Martin Bergen, Managing Director of the German initiative securPharm, the pharma supply chain is still secure in Europe. But the situation is changing. Especially, as more money can be gained with falsified Viagra than with cocaine. And the sanctions are much less severe which enhances the attraction of falsifying medicines even more and also increases the risk for the safety of medicinal products in Europe. The EU reacted to this with Directive 2011/62/EU already in 2011 and with further clarifications with the Delegated Regulation in 2016 and with the FAQ document 2018. They contain two safety features: the unique serial number and the so called temper-proof-evidence, an anti tampering device on the packaging, proving its integrity.

Accordingly, Martin Bergen put the focus of his lecture at the Packaging Conference on the award of unique serial numbers and their management. SecurPharm has started the corresponding German pilot project and also defines the coding rules.

The central element of the system (national repository) is the database which awards the serial numbers and manages and deletes them when used (i. e. when the pharmacy dispenses the medicinal product). The database has two access points: one for the medicinal product manufacturers managed by ACS Pharmaprotect and one for the pharmacies managed by the German NGDA (Netzgesellschaft Deutscher Apotheker - the network of German pharmacists). The GS1 standard and the IFA standard are the coding standards approved by securPharm for the coding of the unique serial numbers by datamatrix code. GS1 is more widely spread but IFA is less expensive and therefore a possible alternative. The timeline - the date when the new safety features become mandatory - was of great interest. According to Mr. Bergen, the 9. February 2019 will be the central day. But it will still be possible to sell released medicinal products. It will only be required for new products to have the 2D code for their release. It is clear that there will be a period of time when two sorts of the same medicinal product will be stored in pharmacies: with and without safety features. According to Martin Bergen the German pilot project which started in 2013 is successful. But there are also problems - such as the indication "unique identifier is not known" in the pharmacy. In this case the relevant marketing authorisation holder simply forgot to upload the used identification numbers in the database system. But this doesn't matter as we are still in the pilot or learning phase, says Martin Bergen.

Find out more about the lectures in the areas Containment and water for injection (WFI) - in the next issue of the GMP Journal. To learn more about the Pharma Congress please visit


Dr Robert Eicher
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma technology.

As Operations Director
Dr Andreas Mangel

organises and conducts courses and conferences for the ECA Academy in the areas sterile production and computer validation

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