Adrian Kirk

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recently closed consultation on its draft guidance, ICH Q10 Pharmaceutical Quality System. If all goes to plan, adoption could come as soon as Spring 2008. 

The ICH began its work on formulating Q10 when it set the ICH Quality Vision in 2003. The ambition was to create a regulatory framework based on a harmonized pharmaceutical quality system that would be applicable across the life cycle of the product, with an emphasis on an integrated approach to quality risk management and science.  

A key point about ICH Q10 is the desire to apply the ICH vision to the entire product life cycle (i.e., pharmaceutical development, technology transfer, manufacturing, product discontinuation). It is proposed that firms that employ quality by design (ICH Q8 Pharmaceutical Development)

  and risk-management principles (ICH Q9 Quality Risk Management)

  will have a robust quality system to manage change and continual improvement. This should reduce the requirement for post-approval filings and give manufacturers more control over their own destiny, reducing the obstructions that regional variation to regulation can sometimes place over innovation, process improvement and new product launches.  

As the draft guidance itself states: "Implementation of ICH Q10 throughout the product life cycle should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities." 

By creating ICH Q10, the ICH openly admits that, in one sense, it has created nothing new. Rather, ICH Q10 describes an approach to an effective pharmaceutical quality system that is based on ISO concepts, includes applicable GMP regulations, and complements ICH Q8 "Pharmaceutical Development" and ICH Q9 "Quality Risk Management".  

ICH Q10 is a model for a pharmaceutical quality system, and much of the content applicable to manufacturing sites is already specified by regional GMP requirements. The draft guidance specifically states that "ICH Q10 is not intended to create any new expectations beyond current regulatory requirements", and anything within ICH Q10 that is additional to current GMP requirements is "optional" rather than obligatory. Though not specifically referenced in ICH Q10, it should come as no surprise that there are elements of other quality systems mirrored within it. 

From our perspective as a contract laboratory, our quality systems are based on the International Standard ISO/IEC 17025 for the General Requirements for the Competence of Testing and Calibration Laboratories. The management system requirements in ISO/IEC 17025 are written in language relevant to laboratory operations and meet the principles of ISO 9001:2000 Quality Management Systems Requirements. They are also aligned with its pertinent requirements. 

Table 1 demonstrates the common themes between ISO 9001, ICH Q10, ISO/IEC 17025 and what could, no doubt, appear in other quality management system (QMS) standards. 

The adoption of ISO/IEC 17025 is a relatively unique position for a pharmaceutical testing laboratory. However, RSSL comes from a background as a food testing laboratory (accredited to ISO/IEC 17025) and therefore used the fundamentals of that system as the foundation of its GMP system. Most pharmaceutical labs will only have GMP, but as stated above, there are similarities between all QMSs. 

One of the main rationales behind Q10 is the idea that a modern quality system, coupled with the manufacturing process, product knowledge and the application of effective risk-management practices, can help manufacturers change facilities, equipment and processes without the need for prior approval or regulatory submissions. There is also an assumption that using an effective quality system to lower the risk of manufacturing problems should result in shorter and fewer regulatory inspections. 

From a purely financial perspective, some have argued that savings will come from improved process performance, a reduction in cost of internal failures, a reduction in the costs that might otherwise be incurred from delayed implementation of improvements, and a reduction in the cost of preparing and reviewing post-approval submissions.

There may be expenditures involved with implementation, but there can be few manufacturers that do not already have many, if not all, of the elements on ICH Q10 in place via existing QMSs. 

A potential complication for ICH Q10 is the use of subcontractors for any part of the manufacturing process that can be outsourced. If an activity is outsourced, it will be necessary to ensure that the subcontractor follows the required elements of Q10 to a sufficient standard.  

There are two main approaches to this conundrum. The first is to have a formal contract with the subcontractor, which would be agreed between the two parties and detail the responsibilities the subcontractor must meet. This is already a requirement of European GMP, and is also the approach detailed in ICH Q10. An alternative approach would be an audit of the subcontract, where the subcontractor's approach to the requirements of Q10 are reviewed in person. Again, the right to audit a subcontractor is already permitted by GMP regulations. 

That said, adopting a unified approach to QMSs across the regions could prove to be very beneficial. We can envisage best practice discussions with common outcomes, regardless of the continent in which the company is based. Rationalized outcomes to the requirements of Q10 could cause regulatory agencies to have similar expectations, which would stop the possibility of various approaches to the same quality requirement. 

The deadline for public comment on ICH Q10 has now passed and the comments will be delivered to the ICH meeting in Spring 2008 in Brussels. Step 2 of the ICH process is for the ICH Steering Committee to agree that there is sufficient scientific consensus on the technical issues for the draft guideline, or recommendation, to proceed to step 3 — the next stage of regulatory consultation. Step 4 will be the adoption of the ICH guideline, which is reached when the ICH Steering Committee agrees, on the basis of the report from the regulatory Rapporteur of the Expert Working Group, that there is sufficient scientific consensus on the technical issues. This will shortly be followed by implementation or Step 5. 

1. International Conference on Harmonisation, ICH Q8:  Pharmaceutical Development, November 2005. 

2. International Conference on Harmonisation, ICH Q9: Quality Risk Management, November 2005. 

3. International Conference on Harmonisation, Draft  Consensus  Guideline, ICH Q10: Pharmaceutical Quality System, May 2007. 

4. Joint ISO-ILAC-IAF Communiqué on the Management Systems Requirements of ISO/IEC 17025:2005, General requirements for the competence of testing and calibration laboratories, (2005).

5. International Conference on Harmonisation, Quality Systems, Gerry Migliaccio Pfizer Inc, AAPS Workshop — Pharmaceutical Quality Assessment, October 2005. 

6. FDA, Guidance for Industry: Quality Systems Approach to  Pharmaceutical CGMP Regulations, September 2006. 

Articles

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recently closed consultation on its draft guidance, ICH Q10 Pharmaceutical Quality System. If all goes to plan, adoption could come as soon as Spring 2008.

ICH seeks harmony on quality

On 12 October 2006, Volume 71 of the Federal Register announced that FDA had published its 

Guidance for Industry on Investigating  Out-of-Specification (OOS) Test Results for Pharmaceutical Production

  It replaced the draft guidance, which had been available since November 1998.  

The new guidance features several updates following responses received on the draft guidance. Most significantly: 					

The scope and background was revised to clarify the applicability of the document.

The section on investigating OOS results, averaging, and concluding the investigation was reorganized. 

Specific guidance on certain issues was added or clarified.

Hence, the guidance addresses investigations of OOS results in the laboratory phase, including responsibilities of the analyst and supervisor, and when indicated, the expansion of an investigation outside of the laboratory to include production processes and raw material as appropriate. The guidance is intended to apply to traditional methods of drug product testing and release, based on testing of discrete samples of in-process materials and finished products. 

A few definitions have been expanded to broaden the scope of the term OOS results. In the 1998 guidance document, the term OOS results included "all suspect results that fall outside the specifications or acceptance criteria established in new drug applications, official compendia, or by the manufacturer". 

In the latest guidance, this definition has been expanded to include "all test results that fall outside the specifications or acceptance criteria established in new drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications". 

The growth of contract analytical laboratories (CALs) performing production and/or testing responsibilities for pharmaceutical companies has also been taken into account with the inclusion of a statement that the guidance notes can be used by contract firms within Section I: The Introduction.  

Contract firms are specifically mentioned later too. In Section II, it states: "The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm." Later in Section III, it is stated: "For contract laboratories, the laboratory should convey its data, findings and supporting documentation to the manufacturing firm's quality control unit (QCU), who should then initiate the full-scale OOS investigation."  

These two statements do appear to somewhat contradict each other, suggesting on the one hand that the CAL has equal responsibility with the manufacturer, and on the other that it is only ever responsible to the manufacturer. In practice, of course, investigation of OOS results is usually a mutual decision, prompted by the reporting of results by the CAL, proposal of follow up investigation by one or both parties and agreement of the contractual basis on which the work is being performed. 

The new guidance is surprisingly lacking in detail as to how OOS results should be classified and followed up. It merely notes that: "The source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process." 

From the laboratory's perspective it is far more useful to drill down to the detail and assign the error more specifically, for example, dilution error or wrong sample weight used. Our own laboratories would always seek to assign a conclusion to any investigation; that is, calculation error, method error, equipment error, technician fault or genuine OOS. This affords the opportunity to analyse OOS results for specific trends to highlight potential weaknesses in our own quality system, and provides greater assurance to the client that an OOS result reported as arising from manufacturing error is indeed genuine. 

To be fair, Section III of the guidance states that "corrective action to prevent recurrence" should occur whenever laboratory error is identified as being the cause of an OOS result. However, Iam in favour of the term "preventive action", which is used later in the section.  

The responsibilities of the laboratory supervisor have been expanded slightly. The new guidance makes the observation that the supervisor should verify the calculations used to convert raw data values into final test results and verify that automated calculation methods have not been invalidated. These details have been included to cover the now frequent use of spreadsheets, which are considered validated by having a password applied to protect the calculations within the worksheets. 

Section IV of the guidance document concerns the full-scale OOS investigation; that is, where the laboratory has shown that there has been a fault in the production process. The latest guidance states that the investigation may consist of a production process review, as well as additional laboratory work, if required. Minor updating of wording includes looking for the "root cause" of the OOS result within the production process, rather than its "source". 

This section has been chiefly rewritten. "General Investigational Principles" and "Laboratory Phase of an Investigation" in the draft guidance have been replaced with "Review of Production", "Additional Laboratory Testing" and "Reporting Testing Results". It is interesting that some words have been added to this section. For example, in a discussion of how firms deal with OOS situations, the old guidance used to say that: "Some firms use a strategy...". In the new guidance, this sentence now reads, "FDA inspectors have revealed that some firms use a strategy...". It is tempting to conclude that these few extra words expose a much more significant truth, viz, FDA makes close examination of OOS investigations during its routine audits of laboratory and manufacturing facilities. 

The draft guidance stated that "testing into compliance is objectionable". The updated version is more damning of any such practice. The wording has been expanded to state that "testing into compliance is unscientific and objectionable." The indication of "unscientific" gives gravitas to the entire process being a thorough, logical investigation. 

This is confirmed within the guidance. In the section on "Additional Laboratory Testing", which makes it clear that when there are no laboratory or calculation errors identified and there is no scientific basis for invalidating the initial OOS results in favour of acceptable retest results, then "All test results, both passing and suspect, should be reported". Later, in the section on "Reporting Testing Results", the guidance details, "It is critical that the laboratory provides all individual results for evaluation" as "averaging the result(s) of the original test that promoted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate." This practice "hides variability" according to the guidance and furthermore, "relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specification." Anyone familiar with the USA v Barr Laboratories case of 1993 will recognize the importance of not ignoring OOS results, and the inappropriateness of testing into compliance.  

The role of the manufacturer's QCU is reiterated in Section V: Concluding the Investigation. The 1998 draft document made no reference to who should evaluate the batch. The new guidance places that responsibility firmly on the QCU by stating, "release decision should be made by the QCU" and "the QCU is responsible for interpreting the results of the investigation." 

Current practice amongst CALs is to issue the client with a copy of the OOS investigation report, with the master copy being retained in case of a regulatory inspection. There was no specific instruction in the draft guidance that this should occur and the 2006 guidance only states that it is "recommended that OOS investigation reports be provided to the customer".  

The updated guidance has only been in circulation for a short while and needs to be further assessed and reviewed by industry. Although, no longer technically at draft stage, comments can still be passed to FDA via the usual routes, and there are already training courses and seminars where the guidance has prompted much discussion. 

is the quality manager of RSSL Pharma (UK). 

1. Guidance for Industry Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. 

Anyone familiar with the USA v Barr Laboratories case of 1993 will recognize the importance of not ignoring OOS results, and the inappropriateness of testing into compliance.