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. Thequestion mark can now be replaced by an exclamation mark. ICH Q10"Pharmaceutical Quality Systems" that was announced a while ago already, was nowpublished in step 2. The new guideline which has to be seen in direct connectionwith ICH Q8 and Q9 implements ISO quality standards in pharmaceutical qualitysystems.

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

  • 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 improvementprocess (KVP), a typical element in the ISO quality standard.

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

In general, ICH Q10 does not want to set up new requirements beyond thosethat already exist. That's why the parts that are included in addition to thecurrent GMP regulations are rather options – according to the wording in ICHQ10!

The new guideline addresses API manufacturers as well as pharmaceuticalcompanies, and includes the complete product life cycle – from API developmentto phasing out of the product. The pharmaceutical quality system centres on thethree 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" andmanagement responsibilities ICH Q10 is supposed to build a bridge to nationalregulations.

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

  • 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-chaptersthat are mostly known from ISO standards:

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

In chapter 3 – "Continual Improvement of Process Performance and ProductQuality" 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 ISOelements. In addition the following steps are mentioned for a life cycleapproach:

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

Four tables show application areas of a process performance and productquality monitoring system, of CAPA and change management as well as of themanagement review – each in the product life cycle. According to the newguideline there is an advantage in a better process understanding as well as ina modern approach to a process validation. However, ICH Q10 does notsubstantiate this proposition.

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


Technology Transfer


Product Discontinuation

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

Monitoring of scale-up activities can provide a preliminary indicationof process performance and the successful integration intomanufacturing. Monitoring of transfer and scale-up activities can beuseful in further developing the control strategy.

Awell-defined system for process performance and product qualitymonitoring should be applied to assure performance within a state ofcontrol and to identify improvement areas.

Once manufacturing ceases, monitoring such as stability testing shouldcontinue to completion of the studies. Appropriate action on marketedproduct should continue to be executed according to regionalregulations.

ii) Corrective Action and Preventive Action System (CAPA)

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

Table II: Application of Corrective Action/Preventive Action throughout theProduct Lifecycle


Technology Transfer


Product Discontinuation

Product or process variability is explored. CAPA methodology can beuseful where corrective actions and preventive actions are incorporatedinto the iterative design and development process.

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

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

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

iii) Change Management System

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

The change management system ensures continual improvement is undertaken in atimely and effective manner while providing a high degree of assurance there areno unintended consequences of the change.

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

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

(2) All changes should be properly evaluated. Proposed changes should beevaluated relative to the marketing authorisation, including design space, whereestablished, and / or current product and process understanding. As stated inICH Q8, movement within the design space is not considered a change (from aregulatory filing perspective). However, from a pharmaceutical quality systemstandpoint, all changes should be evaluated by a company's change managementsystem;

(3) Proposed changes should be evaluated by expert teams contributing theappropriate expertise and knowledge from relevant areas, e.g., PharmaceuticalDevelopment, Manufacturing, Quality, Regulatory Affairs and Medical, to ensurethe change is technically justified. Prospective evaluation criteria for aproposed change should be set;

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

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

Table III: Application of Change Management System throughout ProductLifecycle


Technology Transfer


Product Discontinuation

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

The change management system should provide management and documentationof adjustments made to the process during technology transferactivities.

Aformal change management system should be in place for commercialmanufacturing. Oversight by the quality unit should provide assurance ofappropriate science and risk based assessments.

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

iv) Management Review of Process Performance and Product Quality

Management review should provide assurance that process performance andproduct quality are managed over the lifecycle. Depending on the size andcomplexity of the company, management review can be a series of reviews atvarious levels of management and should include a timely and effectivecommunication and escalation process to raise appropriate quality issues tosenior levels of management for review.

(1) The management review system should include:

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

(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 fromcorrective 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 ProductQuality throughout the Product Lifecycle


Technology Transfer


Product Discontinuation

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

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

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

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

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

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

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

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


Potential Opportunity

1.Comply with GMPs

Compliance – status quo

2.Demonstrate effective pharmaceutical quality system, including effectiveuse 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 useof 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 andprocess understanding, including the use of quality risk managementprinciples (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 tomaximize 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 qualitystandards that much. However, ICH understands "requirements" beyond establishedGMP regulations as option. Mid of the 90s these ISO standards were clearlycontroversial – quite many definitely argued against an ISO 9000ffcertification. 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 standardelements in GMP? De facto many companies in the GMP environment alreadyintegrated ISO elements in their quality management systems. Further, managementreviews are absolutely common in the industry. Moreover, CAPA is alsoincreasingly employed. Almost all pharmaceutical companies already establishedquality manuals or – as ICH Q10 specifically approves – similar documents aswell. 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 smooththe way between the regions. Possibly, a worldwide harmonisation of "GMP formedicinal products" as an ICH guideline Q7X – similar to the very successful ICHQ7A "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients" –would be more helpful. Also, a certain redundancy is noticeable in the entiredocument. Maybe future ICH steps can help to clean the document.

The complete document is available here.

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

ICH Q10 – Discussion with Representatives from the ICH Q10 Expert WorkingGroup

A member of the ICH Q10 Expert Working Group (Dr. JacquesMorénas from the French authority AFSSAPS) will introduce the document at the 2nd European GMP Conferencein Heidelberg, Germany, on 25/26 June. The new developments will be part of aseparate session. The conference is organised by the European Compliance Academy(ECA), the European QP Association and the University of Heidelberg. Altogether24 speakers – from EMEA, FDA, other members of the ICH Expert Working Groupsand others – will provide information on the latest developments.

Quality management systems are also in the centre of the ECA education courseGMP and FDA compliantQuality and Documentation Systems inCopenhagen on 22/23 October 2007.

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


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