ICH Publishes Q10 Guideline as Step 2

GMP News
31 May 2007
 

ICH Publishes Q10 Guideline as Step 2

 
"GMP goes ISO?" This question was posed in an article end of the 90s. The question mark can now be replaced by an exclamation mark. ICH Q10 "Pharmaceutical Quality Systems" that was announced a while ago already, was now published in step 2. The new guideline which has to be seen in direct connection with ICH Q8 and Q9 implements ISO quality standards in pharmaceutical quality systems.

In a nutshell the ICH Q10 guideline is structured in five chapters and an annex:

  • Pharmaceutical Quality System
  • Management Responsibilities
  • Continual Improvement of Process Performance and Product Quality
  • Continual Improvement of Pharmaceutical Quality System
  • Glossary
  • Annex 1
  • This structure already shows the concentration on a continuous improvement process (KVP), a typical element in the ISO quality standard.

    In the introduction to chapter 1 ("Pharmaceutical Quality System") it is also mentioned that ICH Q10 describes an approach to pharmaceutical quality systems based on ISO quality management system concepts. However, it also incorporates GMP regulations and complements ICH Q8 and Q9. Elsewhere the document also refers to ICH Q7A as an element that was also included.

    In general, ICH Q10 does not want to set up new requirements beyond those that already exist. That's why the parts that are included in addition to the current GMP regulations are rather options – according to the wording in ICH Q10!

    The new guideline addresses API manufacturers as well as pharmaceutical companies, and includes the complete product life cycle – from API development to phasing out of the product. The pharmaceutical quality system centres on the three issues

    • Product realisation
    • Development and establishment of a process control and the
    • Continuous product improvement process

    These three activities can only be realised through "knowledge management" and "quality risk management". Including specific "quality system elements" and management responsibilities ICH Q10 is supposed to build a bridge to national regulations.

    The new guideline now also refers to a "quality manual" (or a similar documentation), another typical ISO element – with the following expected content:

    • A quality policy
    • A description of the quality system scope
    • An identification of processes (supported by process maps and flow diagrams)

    Chapter 2, "Management Responsibilities", is structured in seven sub-chapters that are mostly known from ISO standards:

      2.1 Management Commitment – this chapter concentrates on the management's commitment to get involved in the development of the quality system and its improvement and to provide appropriate resources.
      2.2 Quality Policy (also noting continuous improvement).
      2.3 Quality Planning – in addition to training and others it is also suggested to use key performance indicators to measure quality goals.
      2.4 Resource Management – management is asked to provide sufficient resources (like personnel, finance, materials, space and equipment)
      2.5 Internal Communication – an appropriate communication process is required, covering all levels.
      2.6 Management Review – is understood as an appropriate means to evaluate adequacy and effectiveness of the quality system.
      2.7 Oversight of Outsourced Activities – the QM system has to include external activities as well.

    In chapter 3 – "Continual Improvement of Process Performance and Product Quality" four elements are repeated supporting the life cycle approach:

    • Process performance and product quality monitoring
    • CAPA
    • Change Management
    • Management Review

    Again, this chapter also includes CAPA and management review as typical ISO elements. In addition the following steps are mentioned for a life cycle approach:

    • Pharmaceutical Development (again specifically indicating ICH Q8)
    • Technology Transfer (seen as a basis for process control, process validation and KVP)
    • Manufacturing
    • Product Discontinuation (describing activities with regard to phasing out a product like document archiving or complaint management)

    Four tables show application areas of a process performance and product quality monitoring system, of CAPA and change management as well as of the management review – each in the product life cycle. According to the new guideline there is an advantage in a better process understanding as well as in a modern approach to a process validation. However, ICH Q10 does not substantiate this proposition.
        

    Table I: Application of Process Performance and Product Quality Monitoring throughout the Product Lifecycle

    Development

    Technology Transfer

    Manufacturing

    Product Discontinuation

    Quality risk management and monitoring conducted throughout development can be used to establish a control strategy for manufacturing.

    Monitoring of scale-up activities can provide a preliminary indication of process performance and the successful integration into manufacturing. Monitoring of transfer and scale-up activities can be useful in further developing the control strategy.

    A well-defined system for process performance and product quality monitoring should be applied to assure performance within a state of control and to identify improvement areas.

    Once manufacturing ceases, monitoring such as stability testing should continue to completion of the studies. Appropriate action on marketed product should continue to be executed according to regional regulations.

    ii) Corrective Action and Preventive Action System (CAPA)

    The pharmaceutical company should have a system for implementing corrective actions and preventive actions resulting from the investigation of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. A structured approach to the investigation process should be used with the objective of determining root cause. The level of effort and formality of the investigation should be commensurate with the level of risk. CAPA methodology should result in product and process improvements and enhanced product and process understanding.

    Table II: Application of Corrective Action/Preventive Action throughout the Product Lifecycle

    Development

    Technology Transfer

    Manufacturing

    Product Discontinuation

    Product or process variability is explored. CAPA methodology can be useful where corrective actions and preventive actions are incorporated into the iterative design and development process.

    CAPA can be used as an effective system for feedback, feed forward and continual improvement.

    CAPA should be used and the effectiveness of the actions should be evaluated.

    CAPA should continue after the product is discontinued. The impact on product remaining on the market should be considered as well as other products which might be impacted.

    iii) Change Management System

    Innovation, continual improvement, the outputs of process performance and product quality monitoring and CAPA drive change. In order to properly evaluate, approve and implement these changes, a company should have an effective change management system. There is generally a difference in formality of change management processes prior to the initial regulatory submission and after submission, where changes to the regulatory filing might be required under regional requirements.

    The change management system ensures continual improvement is undertaken in a timely and effective manner while providing a high degree of assurance there are no unintended consequences of the change.

    The change management system should include the following, as appropriate for the stage of the lifecycle:

    (1) Quality risk management should be utilised to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk. There should be an assessment to determine whether a change to the regulatory filing is required under regional requirements;

    (2) All changes should be properly evaluated. Proposed changes should be evaluated relative to the marketing authorisation, including design space, where established, and / or current product and process understanding. As stated in ICH Q8, movement within the design space is not considered a change (from a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all changes should be evaluated by a company's change management system;

    (3) Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas, e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs and Medical, to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set;

    (4) After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on product quality;

    (5) Regional regulatory submission/approval requirements should be assessed for a proposed change to a marketed product.

    Table III: Application of Change Management System throughout Product Lifecycle

    Development

    Technology Transfer

    Manufacturing

    Product Discontinuation

    Change is an inherent part of the development process and should be documented; the formality of the change management process should increase as the product moves through development.

    The change management system should provide management and documentation of adjustments made to the process during technology transfer activities.

    A formal change management system should be in place for commercial manufacturing. Oversight by the quality unit should provide assurance of appropriate science and risk based assessments.

    Any changes after product discontinuation should go through an appropriate change management system.

    iv) Management Review of Process Performance and Product Quality

    Management review should provide assurance that process performance and product quality are managed over the lifecycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review.

    (1) The management review system should include:

    (a) The results of regulatory inspections and findings, audits and other assessments;

    (b) Periodic quality reviews, that can include:

    (i) Measures of customer satisfaction such as customer complaints and recalls;

    (ii) Conclusions of process performance and product quality monitoring;

    (iii) The effectiveness of process and product changes including those arising from corrective action and preventive actions.

    (c) Any follow-up actions from previous management reviews;

    (2) The management review system should identify appropriate action, such as:

    (d) Improvements to manufacturing processes and products;

    (e) Provision, training and/or realignment of resources;

    (f) Capture and dissemination of knowledge.

    Table IV: Application of Management Review of Process Performance and Product Quality throughout the Product Lifecycle

    Development

    Technology Transfer

    Manufacturing

    Product Discontinuation

    Aspects of management review can be performed to ensure adequacy of the product and process design.

    Aspects of management review should be performed to ensure the developed product and process can be manufactured at commercial scale.

    Management review should be a structured system, as described above, and should support continual improvement.

    Management review should include such items as product stability and product complaints.

     
    Chapter 4 ("Continual Improvement of Pharmaceutical Quality System") covers KVP with regard to Pharmaceutical Quality Systems. Key elements are:

    • Management-Review (again indicating Key Performance Indicators)
    • Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System and
    • Outcomes of Management Review and Monitoring

    The repeated integration of ISO quality standards is also shown in the glossary which partly directly refers to ISO 9000-2005 (and to other ICH guidelines as well).

    In a table (Annex 1) various scenarios are used to demonstrate the advantages of implementing ICH Q10 – ideally in combination with ICH Q8 and Q9.
      

    Scenario

    Potential Opportunity

    1. Comply with GMPs

    Compliance – status quo

    2. Demonstrate effective pharmaceutical quality system, including effective use of quality risk management principles (e.g., ICH Q9 and ICH Q10).

    Opportunity to:

    • increased use of risk-based approaches for regulatory inspections

    3. Demonstrate product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8 and ICH Q9).

    Opportunity to:

    • facilitate science-based pharmaceutical quality assessment;
    • enable innovative approaches to process validation;
    • establish real-time release mechanisms.

    4. Demonstrate effective pharmaceutical quality system and product and process understanding, including the use of quality risk management principles (ICH Q8, ICH Q9 and ICH Q10).

    Opportunity to:
    • increased use of risk-based approaches for regulatory inspections;
    • facilitate science-based pharmaceutical quality assessment;
    • optimize science and risk-based post-approval change processes to maximize benefits from innovation and continual improvement;
    • enable innovative approaches to process validation;
    • establish real-time release mechanisms.

     
    Conclusion: It is surprising that ICH Q10 focuses on ISO quality standards that much. However, ICH understands "requirements" beyond established GMP regulations as option. Mid of the 90s these ISO standards were clearly controversial – quite many definitely argued against an ISO 9000ff certification. Only at the end of the decade a first change could be noticed.

    Is the new ICH Q10 guideline the start for implementing ISO quality standard elements in GMP? De facto many companies in the GMP environment already integrated ISO elements in their quality management systems. Further, management reviews are absolutely common in the industry. Moreover, CAPA is also increasingly employed. Almost all pharmaceutical companies already established quality manuals or – as ICH Q10 specifically approves – similar documents as well. Thus many companies are already in the middle of the ICH Q10 process.

    It will be interesting to see whether ICH Q10 will really be able to smooth the way between the regions. Possibly, a worldwide harmonisation of "GMP for medicinal products" as an ICH guideline Q7X – similar to the very successful ICH Q7A "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients" – would be more helpful. Also, a certain redundancy is noticeable in the entire document. Maybe future ICH steps can help to clean the document.

    The complete document is available at: http://www.ich.org/LOB/media/MEDIA3917.pdf

    In expectation of the discussion process the European Medicines Agency (EMEA) published the document with the same content as step 3 at http://www.emea.europa.eu/pdfs/human/ich/21473207en.pdf.
      

    ICH Q10 – Discussion with Representatives from the ICH Q10 Expert Working Group

    A member of the ICH Q10 Expert Working Group (Dr. Jacques Morénas from the French authority AFSSAPS) will introduce the document at the 2nd European GMP Conference in Heidelberg, Germany, on 25/26 June. The new developments will be part of a separate session. The conference is organised by the European Compliance Academy (ECA), the European QP Association and the University of Heidelberg. Altogether 24 speakers – from EMEA, FDA, other members of the ICH Expert Working Groups and others – will provide information on the latest developments.

    Quality management systems are also in the centre of the ECA education course GMP and FDA compliant Quality and Documentation Systems in Copenhagen on 22/23 October 2007.

     
    Author:
    Sven Pommeranz
    On behalf of the European Compliance Academy (ECA)
     

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