[Stability Testing related News – vol.19]

◆ The integrity of GMP data – part 2 of the new MHRA blog (12-Aug-15 ECA)

  To the MHRA, data integrity is a significant, high priority theme right now. Above and beyond the existing Data Integrity Guidelines, the MHRA developed a new blog on the theme in June.

The second blog went live on 16 July 2015. It is all about the design of systems with which the quality and integrity of data can be ensured. This applies to both paper and computerised systems.

A helpful, data-integrity-related acronym is ALCOA.
ALCOA stands for ‘attributable’, ‘legible’, ‘contemporaneous’, ‘original’ and ‘accurate’ as indicators of data administration system success. It includes the following aspects:

Attributable
The identity of the person who made the entry must be unique and obvious.

Legible
It should not be possible to modify or restore records without an audit trail. And it is important not to forget paper records.

Contemporaneous
The records must be at the right place at the right time. This principle is illustrated using an example from the field of packaging operations.

Original
The original data must preserve data accuracy, completeness, contents and meaning, including the meta data.

Accurate
Recording the data automatically with the necessary IT controls guarantees better overall control. In cases where automation is not possible, real-time verification by a second employee for quality-relevant values may be necessary.

 

◆ New USP proposal for updating identity checks in U.S. Pharmacopeia (19-Aug-15 ECA)

  In the Pharmacopeial Forum 41(2), an article entitled ‘Stimuli to the Revision Process’ on the modernisation of the general chapter on identity checks <191> has been published in USP/NF. The same issue of PF 41(2) also contains the proposal to revise this existing general chapter <191>.

The chapter <191> treats the identification of ions or counterions in active substances that exist as salt compounds. The plan is to replace the existing flame test from <191> since it is not particularly meaningful. In future, selecting the options for identity checks in chapter <191> will be more flexible. Users will be able to apply other methods as long as they have been properly validated.

The following instrumental methods are being considered:

• X-ray fluorescence (XRF) 
• Atom spectrometry (AA) 
• ICP-OES 
• ICP-MS 
• IR 
• Raman 
• Ion chromatography

Other methods can also be used. However, the prerequisite here is that the user must document the specificity of a method as part of the validation.

For detailed information on the USP proposal, please see the USP website of Pharmacopeial Forum (PF).

 

◆ Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7 (16-Sep-15 ECA)

  Active Pharmaceutical Ingredients Committee (APIC) recently published therevised “How to do” document as “Version 8” on the APIC publications website in August 2015. As compared to the last revision (August 2012) the chapters 10 “Storage and Distribution”, 11 “Laboratory Controls”, 12 “Validation” and 15 “Complaints and Recalls” were revised. The following is a selection of the most important changes:

Chapter 10 Storage and Distribution

• This chapter points out the importance of controlling the temperature distribution in warehouses taking into account seasonal temperature changes. The document indicates sets of rules that describe concretely how to perform a temperature mapping (section 10.10.). 
• It stresses the necessity of physical separation between released and returned material, preferably by storing them in different rooms. Storage conditions for intermediates are based on development data and knowledge (section 10.11). 
• The document points out that logistics companies should be qualified (quality agreement). The shipping conditions records should be reviewed. If deviations occurred an investigation should be initiated and appropriate measures be carried out and documented (section 10.21).

Chapter 11 Laboratory Controls

• This chapter expressly points out that analytical methods have to be validated and that the integrity of analytical data has to be ensured by means of controls (section 11.11). 
• Rounding rules and the process used for averaging should be described in a SOP (section 11.11.). 
• In chapter 11.13 ICH M7 and ICH Q3D have been added to the list of ICH guidelines. Furthermore, it is pointed out that the design of experiments approach can also be used within the framework of design space when defining specifications. 
• Chapter 11.15 contains detailed guidance on the FDA requirements for active pharmaceutical ingredients that are exported to the USA and sold there, especially on the handling of OOS results.

Chapter 12 Validation

• Chapter 12.11 explains more in detail the handling of critical parameters and quality attributes referring to the actual ICH guidelines ICH Q8 and Q11 as well as to FDA and EMA guidelines. 
• It indicates that the 3 consecutive validation batches should be considered as an orientation. The actual number of validation batches has to be pre-defined and to be justified (section 12.50). 
• The process validation report has to contain all critical quality attributes compared to the reference batches. These attributes should be comparable to or better than the reference batches. The rationale for selecting the reference batches must be justified (section 12.52).

Chapter 15 Complaints and Recalls

• This chapter refers to the necessity to include other batches potentially connected with the batch affected by the complaint or recall in the complaint investigation and to define a period to close complaint investigations (section 15.10). 
• It points out that a recall cannot be carried out by the API manufacturer himself. This is the responsibility of the finished dosage form manufacturer. The notification of the authorities (such as public health departments) can also only be carried out in close cooperation with the finished dosage form manufacturer (section 15.10).

As a whole the revised “How to do” document is a valuable aid for the implementation of the Good Manufacturing Practice in the production of active pharmaceutical ingredients. Due to the thorough revision of many sections it offers an up-to-date practice-oriented assistance every API manufacturing site can profit from. You can purchase the APIC ICH Q7 How to do Guide as a side by side comparison to ICH Q7 in the ECA publication shop.

 

◆ Validation – Revision of Annex 15: How does the Industry see the Changes? – Results of an ECA Survey (30-Sep-15 ECA)

  With the publication of a draft on the revision of Annex 15 at the beginning of February 2014, changes in the area of validation/qualification were to be expected. Even then, the ECA Academy started an industry survey (Validation – Revision of Annex 15: Industry’s “problems” – Results of an ECA Industry Survey). Now the final document is published and the changes will become valid on 1 October 2015. But how does the industry see the new requirements?

A total of 53 people took part in the survey and the participants have an overall positive opinion of the revision of Annex 15.

In conclusion, in total 58% consider the document to be very good or good. 28% said the revision is “satisfactory”. Some of the new options are already being used by the industry (e.g. temporary release, combinations of qualification stages).

Easing the requirement for FAT/SAT tests (“could”) compared to the draft was well received. 68.8% find it good.

The new PQ definition is now surprisingly clear (68.2%), on the other hand, almost 1/3 of the participants are still unsatisfied with the definition.

Just as with the survey about the draft, there is still considerable uncertainty regarding the 3 validation batches. Here the industry would like more specific information or to carry on as previously (“always produce 3 batches”).

The hybrid approach is also only clear to just under 50% of participants. With the request for ongoing process verification, the majority of the industry (60.4%) believes this will result in additional work, while 50% also believe discontinuing the routine revalidation will result in additional work.

The analysis of the industry on packaging validation is also varied. Around 1/3 believe this will result in additional work, but almost as many think the opposite and also 1/3 cannot currently say whether any additional work will arise.

The industry is mostly sceptical about the PDE concept in connection with the cleaning validation. For 69.4% the concept is not yet clear and just under 1/5 would like to start pharmacological investigations to calculate PDE values. The industry is dealing very pragmatically with the discontinuation of the three batches during cleaning validation.

69.4% would like to determine the runs based on a risk assessment. The majority of participants believe it conforms with the FDA process validation guidance to a relatively great extent.

Details of the survey will also be discussed at the ECA Annex 15 Conference, which will take place in Berlin, Germany, on 25/26 November 2015.