How should a risk analysis be conducted for contamination in a lyophilization process?

The draft of the European Directive on the Manufacture of Sterile Products – EU GMP Annex 1- published by the EMA in February 2020 has been supplemented by major modifications since its official version published in November 2008. While a new section 8 on “Production & Specific Technologies” now identifies the specific requirements applicable when using technology such as lyophilization, a new section 3 is also dedicated to the Pharmaceutical Quality System (PQS), basing the control of contamination on QRM (Quality Risk Management) [see ref ICH Q9 R1] and formalization of the control strategy in the CCS.

The Annex 1 update responds to a change in sterility control, which is moving from control of contamination of grade A working environments towards closed systems and barrier technologies, effectively displacing the main concerns of microbial and particulate contamination. There are multiple sources and these must be considered in relation to each other, hence the importance of the methodical, systematic and structured character of the QRM to guide the analysis and establish preventive actions (or even detection / remediation actions).

If  the principles of QRM should therefore be applied (see section 1 Scope “QRM applies to this document in its entirety”), how should it be used to determine and control the main contamination risks in a lyophilization process?

1. Reminder of QRM expectations according to Annex 1

  1. In order to minimize microbial contamination and ensure the quality of manufactured sterile products, it will be necessary to have a risk management system covering the entire product life cycle. The approach must apply the 4 steps of the risk management process defined in ICH Q9. (see illustration)

As the appropriateness of risk management is based on science and experience, each manufacturer must have sufficient knowledge and expertise in relation to products manufactured, equipment, engineering and the manufacturing methods employed which have an impact on product quality. Annex 1 itself falls within this principle, and specifies that the specific limits or frequencies indicated should be considered a minimum requirement. They are indicated because of the historic experience of the regulations concerning problems which were identified previously and which had an impact on patient safety. The approach must be systematic and be based on the understanding, among other things, of interactions between product, process and equipment: we are indeed at the heart of a Quality by Design approach.

2. Which types of contamination are possible in a lyophilization process?

To illustrate the implementation of QRM, we will rely on the study of a case that is frequently encountered: batch lyophilization with loading of partially stoppered vials and unloading of stoppered vials in the lyophilizer.

As emphasized by the ISO 13408-3:2006 standard, given that lyophilization is often the last step in an aseptic process with a direct impact on the safety, quality, identity, efficacy and purity of a product, lyophilization is an essential step in aseptic processing.

In the case of the manufacture of sterile injectable lyophilized products, we seek to guarantee the prevention of microbiological contamination (molds, bacteria, viruses), particulate contamination, and contamination by pyrogens in the final product.

The lyophilization process and its technology must be designed to control the different types of contamination. Indeed, the technologies currently available impose by design the presence of sources of potential chemical contamination inside the lyophilizer chamber. We can cite for example: the coolant circuit of the shelf heating system or that of the stoppering system. A leak of fluid may lead to the generation of aerosols according to temperature and pressure conditions during the different drying phases within the lyophilizer.

As lyophilization has this specific feature of intentionally using several utilities (air, nitrogen gas, steam for example…), these all represent sources of potential contamination, that we may consider contamination sources that are generic to the utilities in question. To secure the use of these sources, it will be necessary to implement a QRM approach in the design, installation and use of the lyophilizer with regard to these utilities.

Moreover, if we consider all lyophilization process operations, the loading / unloading operation is the one that presents a significant risk, given that the system is no longer closed. Following the filling operations, the loading operation must have barrier technologies as an effective means of contamination control. Following the stoppering operations, the unloading operation requires a Grade A Air Supply, for the protection of fully stoppered vials where the stopper has not yet been crimped. We note that loading/unloading is a pharmaceutical operation of opening/closing a door, which, even if executed under grade A environmental conditions, may lead to questions as to whether the lyophilizer can be considered a closed system, within the meaning of the definition proposed in Annex 1: a closed system is a system in which the sterile product is not exposed to the surrounding environment. We generally observe that although control of contamination of a manufacturing process can be obtained by implementing closed system and/or barrier technologies, the specific features of the lyophilization process fully justify the application of the QRM principles as a way of identifying the sources of risk, of evaluating them scientifically, and finally of implementing suitable control methods.

Beyond the classic case of batch lyophilization with loading of partially stoppered vials and unloading of stoppered vials, QRM must be applied to other process situations (continuous lyophilization, other containers, bulk, etc.) with the same methodological approach but with consideration of the critical quality attributes (CQA) specific to each final product and the specific features of each process.

 

3. How should QRM be applied to a lyophilization process/equipment item?

Even if the QbD approach is not formally stated in Annex 1, control of the basic elements of contamination (CCS) on which QbD is based is a requirement mentioned more than 40 times in the text. We can cite for example: “the frequency of sterilization (which will depend on the design of the lyophilizer) should be justified and documented as part of the CCS” or again “All control measures in place to prevent microbial and particulate contamination between the filling of products to be lyophilized and the end of the lyophilization process must be documented in the CCS”.

The approach for establishing this CCS will enable the expectations of Annex 1, which fixes priorities with regard to QRM, to be met: in the first instance, good design of the facility, of equipment and of the manufacturing process, then implementation of appropriate procedures, and finally monitoring systems which demonstrate that the design and the procedures have been correctly implemented and allow operation in compliance with expectations.

For implementation of the QRM, the new PQS section 3 of Annex 1 reprises the 4 major steps of the ICH Q9 process: “Risk management is applied in the development and maintenance of the CCS, to identify, assess [Step 1], reduce/eliminate (where applicable) and control contamination risks [Step 2]. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk [Step 3]. The risk management outcome should be reviewed regularly as part of on-going quality management, during change control and during the periodic product quality review [Step 4].”

Analyse Risque Contamination Procede Lyo

For the record, the efficacy of a QRM exercise, aside from the methodology, is determined by knowledge of the specific features of the case to which risk management is applied. It involves ensuring the systematics of the investigation of the instance of risk, and stimulating experts (or subject matter experts) in the standpoints to be documented.

For this, the generic mapping of the problem (contamination) and its adjustment to the case (lyophilization) are a basis for questioning (Risk Question) which ensures rigor, exhaustiveness, rapidity and relevance. Thus we make use of the second QRM principle (the level of effort, of  formality and documentation of the QRM process must be proportionate to the level of risk).

In practice, the Mind Map that we use for the CCS (see illustration) guides a common understanding of the process analyzed in terms of risks, and its sub-branches, challenges the sources of risk and guides the definition of control methods.

In the context of application to lyophilization, there emerge in particular recurrent risks that can be categorized by monitoring the various operations conducted in preparation for lyophilization, and  those occurring during and after lyophilization. The table below maps the different risks typical of lyophilization equipment and the nature of contamination that can be observed.

In light of the summary risks listed in the table, modifications to the design of facilities to minimize manual operations reduce the types of contamination. Automation before and after lyophilization improves control of sources of microbial contamination. The installation of loading robots to replace the operator or of an automated loading and unloading system with barrier technology are examples of automation where the operator is kept away from the critical area close to the lyophilizer door. The frequency of cleaning, of sterilization, the leakage level of lyophilizers, work on operator movements are subjects to be assessed as part of this risk mapping. Environmental monitoring, by identifying the points most at risk and the types of control, should be implemented to look for the different types of contamination. Beyond the lyophilization step, it will be wise, to safeguard against the risks of contamination identified in the table, to carry out crimping if possible in-line, immediately after unloading (avoiding intermediate manipulations, of storage of non-crimped stoppered vials on shuttles, trolleys). As mentioned previously, these downstream operations must be conducted under a Grade A Air Supply, for the protection of fully stoppered vials where the stopper has not yet been crimped.

4. Which good QRM practices should be implemented for an effective and robust result?

The application of Quality Risk Management (QRM) provides a systematic approach to allow consolidation of knowledge of the lyophilization step as actually implemented. The challenge is to identify all sources of contamination, and to define the means of risk control appropriate to the context, finally to obtain a very high level of confidence with regard to patient safety. Several mechanisms and  principles form the basis of the risk-based approach, and it is essential to retain them to ensure a robust result and appropriate control provisions.

The incorporation of the exercise in a multi-step approach as illustrated below allows risk rationales to be based on product impact. Firstly, the QRM exercise must fall within the more global context of control of the Critical Quality Attributes (CQA) of the lyophilized products, to take account of the specific features of the products processed, in line with QbD principles. The process risk analysis step documents the critical process parameters (CPP), and the other operating conditions. This step provides the key to the reading of system risks, themselves linked to the technical implementation of the process in a given lyophilizer.

Analyse Risque Contamination Procede Lyo

The method to be used must be appropriate. Generally, for QRM, we recommend adapting a basic tool to the application context. In the case of contamination, it is generally preferable to adopt an HACCP approach as a basis. HACCP is defined in the Codex Alimentarius and reprised by the ISO 22000:2018 reference document (dealing with food safety). It brings efficacy to the exercise by focusing thought on the feared impact. Identification of the CCP (Critical Control Point) allows targeting of the key critical elements to be controlled. The following illustration shows its application to define the CCS.

Analyse Risque Contamination Procede Lyo

The methodological basis could be the Butterfly approach, if the combination of elements needs to be taken into account.

It is important that the QRM exercise is supplied with the available input data, checked and up to date. For the record, HACCP recalls the importance (step 5/12) of checking that the input data are accurate with regard to the reality of in situ design, operations and practices.

The application of Quality Risk Management (QRM) provides robust systematics to permit consolidation of knowledge regarding the lyophilization step as really implemented. It is imperative to set up a (small) team of experts and of process step practitioners. This team must be maintained for all sessions of the QRM Contamination of Lyophilization exercise.

The QRM exercise for lyophilization equipment will focus particularly on a study of the probability of contamination and on detectability. As for all pharmaceutical risk analyses, it will be vital to prioritize control actions that cultivate prevention, by targeting the reduction of the probability that the risk situation will occur.

All sessions of the exercise must be planned and the total time period allocated can be used to limit the debates between experts and to stimulate the convergence of positions. If needed, points for discussion may be out of session and on the basis of the preparation of rationales.  Exercises must be organized so as to ensure a high level of sharing of knowledge and experience with regard to  this operation, in a transparent manner. To ensure that the analysis is robust, the subjectivity of contributors, and the bias of risk estimations, must be offset by appropriate tools (in particular simple rating scales supporting risk reduction decisions), and by aligning the perception of risk of the contributors. This alignment involves a “training” component, to ensure everyone has the same understanding of QRM fundamentals, and a shared risk culture.

Finally, implementation of QRM must be part of a continuous improvement approach. Once the CCS is defined and adopted, this is a question of using the Quality system (PQS) to introduce provisions to monitor control of this step. This monitoring must be based in particular on the  vigilance of operatives by giving them the capacity to detect adverse events (deviations, or “near-miss” events). Training in the process step, as well as the sharing of the established risk analysis, are necessary.

In summary, good QRM practices may be recalled via the check-list below.

Conclusion

In the context of sterile lyophilized product productions, the lyophilization operation is particularly critical in terms of contamination risks, as a result of the potential exposure of the product to multiple sources of contamination, and particularly the addition of environmental conditions, rather than their removal.

Beyond the forthcoming requirements of the future Annex 1 of the EU-GMP, it is clear that the QRM approach, and the structured and systematic implementation of risk analysis and control, are essential to guide the acquisition and understanding of the knowledge of risk phenomena during the lyophilization operation.

To implement the QRM, the tooling of the method, the structuring of, and capitalization on, the specific knowledge of this process operation, in the context specific to each site and workshop, are keys both to the efficacy and the performance of the risk analysis exercise, as well as the maintainability of deliverables.

From our experience, it seems to us important that this implementation of QRM should be adjusted and organized within an approach that takes account of patient risk. This is essential for the confidence that we will have in the maintenance of product sterility, and in turn, in patient safety. It involves avoiding the main pitfalls, some of which led to the revision R1 of ICH Q9 [draft of 18-nov-2021], particularly regarding the inappropriate arduousness of the exercise and the subjectivity of contributions.

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A Gonnier

Antoine GONNIER

antoine.gonnier@aktehom.com

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C Meunier

Christophe MEUNIER

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Acronymes

CCS Contamination Control Strategy

EMA European Medicines Agency

GMP Good Manufacturing Practices

PQS Pharmaceutical Quality System

QbD Quality by Design

QRM Quality Risk Management

SME Subject Matter Expert

Références

EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal Products (Draft)
ICH Q9 R1 – draft du 18-NOV-2021
ISO 13408-3:2006(fr) : Traitement aseptique des produits de santé — Partie 3: Lyophilisation
ISO 22000:2018 : Systèmes de management de la sécurité des denrées alimentaires
HACCP : Hazard Analysis and Critical Control Point (Codex Alimentarius CXC 1-1969)