ICH Q12 Pharmaceutical Product Lifecycle Management – Part II


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For the establishment of Established Conditions (EC), the ICH Q12 guideline proposes two basic approaches.

Parameter-based approach

Minimal approach

A minimal approach, with a limited understanding of the relationship between inputs and resulting quality attributes, will include a large number of inputs (e.g., process parameters and material attributes) along with outputs (including in-process tests).
(Chapter ICH Q12 Guideline)

The minimal approach corresponds to the "traditional"28 approach of process validation according to which three consecutive production batches are produced. As experience has shown a few more analyses are carried out than is customary in the routine manufacture (such as verification of the mixing homogeneity of the powder mixture before compression). Process knowledge and the testing carried out stem from the experience with the product, from knowledge out of reference books on the formulation processes applied respectively (unit operations) and potentially from developments carried out in the past. Usually, CQA and CPP are not known or not addressed as such. Development reports might be available, but usually it is not possible any more to verify the methodology and the reliability of the results (missing data traceability, obsolete methodologies, performance not according to the currently applicable regulations and legal requirements).

Control strategy: In most cases all collectable input variables (CQA) and process parameters (CPP) are recorded for all batches at 100 % because the empirical evidence on process understanding and knowledge is insufficient. Often the purpose of collection is questioned not from a scientific point of view but only from a commercially one (Motto: "We have always done it this way.").

Procedure in the case of an OOS result: In the case of an OOS result it can only be investigated whether the deviation occurred during the manufacture. The effects of this deviation on the OOS parameters often remain a vague assumption, however, since a hypothesis testing is hardly possible due to non-verified relationships and dependencies. A targeted (experimental) investigation is difficult to design. The analysis of causes must often remain unfinished and present possible hypotheses.

Figure 1 shows the situation in the case of a minimal approach. This is a fictitious example of a mixing step to visualise the influence of the active substance and the excipient as well as of the process parameters mixing temperature, mixing time and agitation speed on the particle size distribution and mixing homogeneity of the powder mixture obtained from the manufacturing step.

Figure 1: Situation in the case of a minimal approach shown at the example of the mixing step for the manufacture of a powder mixture

Enhanced approach

An enhanced approach with increased understanding of interaction between inputs and product quality attributes together with a corresponding control strategy can lead to identification of ECs that are focused on the most important input parameters along with outputs, as appropriate. (Chapter ICH Q12 guideline)

The enhanced approach is characterised by a clear understanding of the relationships between the input variables such as specification of active ingredients and excipients (CQA), the environmental and process parameters (CPP) as well as the output variables (product specification). Process understanding and knowledge is gained by means of systematically structured development approaches that are carried out according to the current guidelines and are completely documented. Available development or transfer reports can be classified and used as reliable basis (supportive information). They establish relationships and set limits for all input and output variables.

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Control strategy: Due to this enhanced process knowledge it is not required any more to collect each available information (control) for each batch. It can be dispensed with the collection and recording of non-relevant parameters. On the other hand, there is a high degree of certainty to have collected all really relevant parameters. Since the relationships are known they can be put in relation (mathematically) with each other. The development of control charts is possible that link input and output variables, and a continuous process verification can be carried out.

Procedure in the case of an OOS result: In the case of an OOS result a relationship can be established between the deviations observed and the effects. If no relationship can be established this means that the process understanding for this case of deviation must be further developed. The development department is invited to carry out a targeted investigation of this relationship. This applies even more if a typical OOS result keeps reoccurring.

Figure 2 shows the situation in the case of an enhanced approach. The same example is chosen as in figure 1. In this example it is already known by means of enhanced process knowledge that the active ingredient's particle size distribution has an influence on the particle size distribution of the powder mixture. Consequently, the active ingredient's particle size distribution must be classified as critical quality attribute (CQA). It should be included in the active ingredient's specification and it should be tested in the framework of the control strategy. The particle size distribution of the excipient is irrelevant. Consequently, it is not a CQA and must not be included in the excipient's specification and it needn't be tested.

Figure 2: Situation in the case of an enhanced approach shown at the example of the mixing step for the manufacture of a powder mixture

Moreover, it is known that the parameters mixing time and agitation speed are relevant for the mixing homogeneity and that they must therefore be specified and recorded as critical process parameters (CPP). The mixing temperature is not relevant for the mixing homogeneity. It must not necessarily be recorded and the limits must not necessarily be defined.

Discussion of the parameter-based approach

In summary, the parameter-based approach consists mainly in a fundamental and generic knowledge of the different steps (unit operations) making part of the manufacture of medicinal products. Specific knowledge often exists only in the form of experience with the product itself. Focus of the approach for assessing the quality of the process is the systematic collection and documentation of all possible quality attributes of active substances and excipients (CQA) und of all collectable process and machine parameters (CPP). The available data pool may undergo a trend monitoring, where appropriate. But the importance of individual collected parameters remains partly unclear.

Performance-based approach

In a performance-based approach, ECs could be primarily focused on control of process outputs (e.g., attributes, measurements, responses) rather than process inputs (e.g., process parameters and material attributes). This is enabled by knowledge gained from an enhanced approach, a data-rich environment, and an enhanced control strategy (e.g., models, Process Analytical Technology (PAT)). For example, a performance-based approach could be considered for manufacturing process steps with in-line monitoring of relevant attributes or with feedback controls or optimization algorithms to achieve the relevant targets for that process step. When considering this approach, it is important to ensure that all relevant parameters and material attributes that have a potential to impact product quality are monitored and equipment used remains qualified in order to assure a stable process. […] (Chapter ICH Q12 Guideline)

The performance-based approach is the most progressive approach for gaining process understanding and process knowledge. It requires a systematic and scientific analysis of the process. Individual process steps are well designed and are individually assessed in a process-oriented risk analysis as concerns their criticality. The input parameters CQA and CPP are defined and proven experimentally. Clear, comprehensible and valid development or transfer reports exist.

Initial process validations take account of predetermined areas in their design and are designed in such a way, that worst case conditions are reviewed. Thus, it is guaranteed for the ongoing productions that all batches whose CQA and CPP are within the defined specifications will conform with the end product specification. Concepts such as normal operating range (NOR), design space (DSp), proven acceptable range (PAR), established conditions (EC) are defined and play a role for the process development and for the ongoing production29.

Design spaces are known and defined in experiments (Design of Experiments (DoE))30. It should be noted however that all changes within the design spaces (listed in the marketing authorisation) are neither notifiable nor subject to approval27. This means that they can be implemented within the quality system by means of a simply change control procedure and are not relevant for the marketing authorisation.

Control strategy: Altogether the development of the manufacturing process and an individually coordinated control strategy play a central role. Quality by design is the philosophy. This means that the reliable and constant achievement of the desired product quality has priority.

By this it is no longer necessary to collect all collectable variables (input, output) for each batch. A targeted skip-lot strategy can be used, meaning that not all parameters of a specification are tested for each batch.

Not only the data received for the batch to be released play a role for the batch release. Ongoing trend analyses accompany the batch assessment so that the control strategy always contains a continuous and meaningful process verification (continuous Process Verification (cPV)).

Such a profound process knowledge offers the possibility of using process analytical technology (PAT). This means in principle that a batch release is possible solely based on the knowledge of the data pool collected in the course of manufacturing without having to control the end product analytically (real time release testing (RTRT), parametric release). Such a procedure is interesting for products which are administered to the patient immediately after manufacture, for instance radiopharmaceuticals or processed blood preparations and when final quality control of relevant parameters such as sterility is not possible due to time or the required sample quantities31,32. The revision of Annex 17 EU Guidelines to Good Manufacturing Practice offers the possibility of such a strategy for the use of parametric release for the routine release of products sterilized in their final container without a final sterility test33.

OOS: If parameters (CQA, CPP) are outside the validated area (edge of failure) already during production a non-compliance of the batch manufactured with the specification is expectable. And vice versa the following can be expected with a high statistical certainty: if all parameters are within the specified (and validated) area it can be assumed without further testing of intermediate products or end products that the end product complies with the specification.

Discussion of the performance-based approach

In summary, the performance-based approach is based on a control strategy which has been elaborated on the basis of the process knowledge available. Goal is the prediction that the batch will be in compliance with the specification with a high statistical certainty if all parameters (CQA; CPP) collected during manufacture are in a predefined and by means of development and validation studies ensured area.

Marketing authorisation relevant variation of the established conditions

According to the legal definitions in Article 2 (Definitions) Regulation (EC) No 1234/2008 a variation within the meaning of the Regulation is each variation "to the contents of the particulars and documents" which were made in the application for a marketing authorisation. Details of the variations to the terms of marketing authorisations and the categories of variations (minor variation of type IA, minor variation of type IB, major variation of type II, extension of a marketing authorisation) are defined in the relevant implementation guidelines to Regulation (CE) 1234/2008. For each conceivable variation (relevant to the marketing authorisation) specific conditions and documents to be submitted are pre-defined. The documents to be submitted have to be seen as supportive documents (supportive information). These supportive documents contribute to a variation in the manufacturing process or test procedure in so far as suitable batch verifications, stability studies or validations after a variation prove that the proposed variation does not have a negative impact on the quality, safety or efficacy of the medicinal product. In principle these documents have to be seen as supplement to the development studies "conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use specified in the marketing authorisation application dossier"34.

Figure 3: Decision tree for the reporting of post-approval changes of ECs following the ICH Q12 Guideline (cf ICH Q12 Guideline
Figure 1: Decision Tree for Identifi cation of ECs and Associated Reporting Categories for Manufacturing Process Parameters).

A complete overview over the contents in the CTD that are ECs and the contents which have to be understood as supportive information is given in ICH Q12 Guideline "Appendix 1: CTD sections that contain ECs".

When the ECs are known the question about the way of reporting to the regulatory authority arises for each post-approval change. The ICH Q12 Guideline offers a decision tree (figure 3). This means in principle that all post-approval changes of parameters that have not been identified as ECs are not relevant for the marketing authorisation. They would need to be discussed only in the product quality review (active substances: EU Guidelines to Good Manufacturing Practice, Part II, Chapter 2.6, medicinal products: EU Guidelines to Good Manufacturing Practice, Part I, Chapter 1.10 (v)) as appropriate.

All post-approval changes concerning ECs have to be assessed as concerns their criticality. They need only be notified to the regulatory authority (notification) or be approved ex-ante by the authority (prior approval).

In respect of this proposal in the ICH Q12 Guideline it should be noted that the fundamental categorisation of the post-approval changes to be reported essentially corresponds to EU law but that here EU jurisdiction is relevant (Regulation 1234/2008) and not the ICH Q12 Guideline.

Product Lifecycle Management (PLCM) Document

The PLCM document outlines the specific plan for product lifecycle management that includes the ECs, reporting categories for changes to ECs, PACMPs (if used) and any post-approval CMC commitments. Its purpose is to encourage prospective lifecycle management planning by the MAH and to facilitate regulatory assessment and inspection. The PLCM document should be updated throughout the product lifecycle as needed.
The PLCM document serves as a central repository in the MAA for ECs and reporting categories for making changes to ECs. (Chapter 5 ICH Q12 Guideline)

The PLCM document is new and not enshrined in EU jurisdiction. This document is supposed to be kept as central register throughout the complete product lifecycle, and it contains all ECS as well as their relevance for the marketing authorisation in the case of a post-approval change (notification or prior approval). Furthermore, the post-approval change management protocol (PACMP) and all relevant explanations of the marketing authorisation holder referring to the product quality and to studies to be carried out after the post-approval changes (post-approval CMC commitments) are supposed to be contained in the document. Annex IF of ICH Q12 Guideline contains an example of a PLCM.

Implementation of the ICH Q12 Guideline into the EU’s pharmaceutical regulatory framework

All ICH member authorities and member states are expected to implement the ICH Q12 Guideline. There is already a comprehensive regulatory framework in the EU which would have to be expanded and adjusted to incorporate the ECs as well as the PLCM document. This places the focus on the common technical document (CTD) which has not been changed since its establishment in 2006. A clarification as concerns the distribution of the information on a medicinal product in the dossier for a marketing authorisation application would be helpful in order to be able to distinguish between legally binding between ECs and supportive information.

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For the establishment of the PLCM document it is favourable to take over the variation categories defined in the implementation guidelines to Regulation (CE) 1234/2008.

The concept ECs has to be included in all legal requirements for and guidelines on the implementation of process validations. Establishing meaningful process risk analyses is decisive, regardless of the methodology used. These process risk analyses identify CQA and CPP, present a clear control strategy and make a distinction between ECs and supportive information.

But in the end the implementation of the ICH Q12 Guideline in the daily routine of manufacture and testing means the revision of the existing instructions for the change management. Where appropriate it would be convenient to prepare a separate specification for all product related variations that lists all categories for variations concerning process and analyses customary in the EU in one PLCM document. As basis for all contract manufacturing agreements this PLCM document can then lead to clarity between the contract manufacturer and the customer with regard to variations to be carried out.

A revision of the requirements in the EU Guidelines to Good Manufacturing Practice for the design of product quality reviews also makes sense. Practice has shown that often various parameters (inprocess-controls, results of the testing of finished products) are reported without their relevance being known. For the future a more systematic reporting of ECs should be pursued, usefully also as trend.

Interestingly, no deadline has been set for the ICH member authorities and member states for the implementation of the ICH Q12 Guideline. Therefore, the question remains unanswered when the harmonisation of the requirements concerning variations to the terms of marketing authorisations can actually be expected.

Part I of this article can be read in the previous issue of the GMP Journal (No 32).


About the Author
Dr Martin Melzer, is Principal Consultant at gempex GmbH. Before that, he worked as a GMP/GDP consultant and as a GMP inspector in medicinal products supervision, among other positions.

27 Pharmaceutical Development Q8(R2), ICH harmonized tripartite guideline, Current Step 4 version, August 2009
28 Guideline on process validation for finished products - information and data to be provided in regulatory submissions, EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1, 21 November 2016.
29 Questions and answers: Improving the understanding of NORs, PARs, DSp and normal variability of process parameters, EMA/CHMP/CVMP/QWP/354895/2017, 6 June 2017.
30 Questions and Answers on Design Space Verification, FDA, EMA joint document, EMA/603905/2013, 24 October 2013.
31 Guidance for Industry PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), Office of Regulatory Affairs (ORA), Pharmaceutical CGMPs, September 2004.
32 Reflection Paper: Chemical, pharmaceutical and biological information to be included in dossiers when Process Analytical Technology (PAT) is employed, European Medicines Agency, EMEA/INS/277260/2005, 20 March 2006.
33 Annex17 of the EU Guidelines to Good Manufacturing Practice, Real Time Release Testing and Parametric Release.
34 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67), in the current version, Annex I Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products, Chapter (Pharmaceutical Development).

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