Latest Event Updates

Analytical Lifecycle: USP “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

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Analytical Lifecycle: USP <1210> “Statistical Tools”, Analytical Target Profile and Analytical Control Strategy

The United States Pharmacopeia (USP) is currently undertaking further steps towards a comprehensive analytical lifecycle approach by publishing a draft of a new General Chapter <1210> Statistical Tools for Procedure Validation and two Stimuli Articles regarding Analytical Target Profile and Analytical Control Strategy in Pharmacopeial Forum. Read more about the life cycle concept for analytical procedures.–USP–1210–%22Statistical-Tools%22–Analytical-Target-Profile-and-Analytical-Control-Strategy_15438,15608,Z-PDM_n.html

Following the recently announced elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle” the United States pharmacopeia (USP) is now proceeding in its approach for a comprehensive analytical lifecycle concept. A further step towards this approach is the draft of a new USP General Chapter <1210> Statistical Tools for Procedure Validation which has been published in Pharmacopeial Forum (PF) 42(5) in September 2016. Comment deadline is November 30, 2016.

Additionally, two Stimuli Articles regarding “Analytical Control Strategy” and “Analytical Target Profile: Structure and Application Throughout The Analytical Lifecycle” appeared in the same issue of the PF.

In the draft chapter <1210> Statistical Tools for Procedure Validation, the USP Statistics Expert Committee presents a revision to the proposal of <1210> published in PF 40(5) [Sept.–Oct. 2014]. On the basis of the comments and feedback given by stakeholders, the committee has addressed their concerns about the narrow scope and details on methodology to be used. The chapter is proposed as a companion to general chapter <1225> Validation of Compendial Procedures with the purpose of providing statistical methods that can be used in the validation of analytical procedures. A revision of general chapter <1225>, including a new section on Lifecycle Management of Analytical Procedures, has been published for comment in PF 42(2) in March 2016.

Specifically, the revision clarifies the accuracy and precision calculations while removing specific linearity requirements. Linearity may be inferred from accuracy or other statistical methods as deemed appropriate. The chapter discusses all of the following analytical performance characteristics from a statistical perspective:

  • accuracy,
  • precision,
  • range,
  • detection limit,
  • quantitation limit,
  • and linearity.

Additional related topics that are discussed in the draft include statistical power, two one-sided tests of statistical equivalence, tolerance intervals, and prediction intervals.

Furthermore, up to now, four Stimuli Articles regarding the analytical lifecycle have been published:

and new in PF 42(5)

  • “Analytical Control Strategy”, and
  • “Analytical Target Profile: Structure and Application Throughout The Analytical Lifecycle”.

The Analytical Target Profile (ATP) is the focal point of the lifecycle approach. It is comparable to the Quality Target Product Profile (QTPP) which is defined in ICH Q8. The Stimuli Article emphasizes “that the current approach to development, validation, verification, and transfer of analytical procedures has served the industry well.” The lifecycle approach – comprised of the development (design, stage 1), qualification (stage 2), and monitoring of the performance of analytical procedures (control strategy, stage 3) – is an extension of the current guidance, taking advantage of the learnings from ICH Q8 – quality by design (QbD) concepts. The Article considers in particular the following questions (and provides examples):

  • What is an ATP, and why is it useful?
  • How can the ATP criteria be established?
  • How can an ATP be applied during the three stages of the procedure lifecycle?

According to the article, “an additional advantage of using an ATP is that it can drive the development of a robust control strategy, resulting in better, more consistent performance of an analytical procedure throughout its lifecycle.”

In the Stimuli Article on the Analytical Control Strategy (ACS), the following questions are discussed:

  • What is the ACS?
  • What is the relationship between the ACS and the ATP?
  • What is the quality risk management (QRM) process and how can it be applied to an analytical procedure?
  • How does the ACS apply to the product lifecycle?

Additionally, examples of the following are provided:

  • How to develop an ACS using the QRM process, and
  • How to develop and apply a risk-based replicate strategy to minimize variability.

The USP Expert Panel would appreciate any feedback on the suggested approaches, as well as any alternative approaches for consideration.
Following your registration on the USP Pharmacopeial Forum website you can get to the proposal for general chapter <1210> and the complete stimuli articles. Because of the importance of the new USP chapter <1220>, ECA and USP join forces and organise the first joint event “Lifecycle Approach of Analytical Procedures“, in Prague, Czech Republic, from 8 to 9 November 2016.

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How to document a Product Transfer? Example templates!

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All participants of the GMP training course “Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects.


According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As participant of the GMP education course “Product Transfer” in Berlin, from 25-27 October 2016 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US Variation Guidelines, are also part of the Guideline Manager CD. Due to copyright reasons, this CD is not available for purchase and can only be handed out to participants of the Product Transfer course.

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New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

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The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent.

The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper.

Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Fig. 1

Fig. 1.

Steps and elements of the QbD methodology completed by the authors and applied in the early stage of pharmaceutical development.

“By identifying the critical process parameters, the practical development was more effective, with reduced development time and efforts.”

Edina Pallagi, our QbD evangelist from Hungary shares her team’s experience applying QbD to Dry Powder Inhalation Formulation.

The paper covers:

  • QbD methodology the researchers applied
  • Formulation of dry powder inhalation – API and excipients
  • QTPP, CQA and CPPs  identified for pulmonary use along with target, justification and explanation
  • Characterization test methods
  • Knowledge Space development
  • QbD software used

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

  • a Institute of Drug Regulatory Affairs, University of Szeged, Faculty of Pharmacy, Szeged, Hungary
  • b Department of Pharmaceutical Technology, University of Szeged, Faculty of Pharmacy, Szeged, Hungary


ECA Task Force will publish Draft Data Integrity Guideline at Conference in October

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Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. For that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice. Read more about the ECA Guidance on Data Integrity.

Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. This is why the topic is currently in the centre of attention of both regulators and industry. And for that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice.

The ECA Task Force will be comprised of members from both the IT Compliance Group and the Analytical QC Group. Current Members are:

– Dr. Wolfgang Schumacher, Hoffmann-La Roche, Switzerland
– Dr. Chris Burgess, Qualified Person and Consultant, UK
– Dr. Bob McDowall, Consultant, UK
– Ms. Margarita Sabater, ALK-Abelló A/S, Denmark

The Task Force decided to develop a Guidance entitled: “Data Governance and Data Integrity for GMP Regulated Facilities“. The ECA Guidance Document will cover – among others – the Roles and Responsibilities of Corporate and Senior Management in Data Governance as well as the necessary Policies, Procedures and Processes. Further information is provided on establishing criteria for Data Integrity and security of records based on ALCOA+Principles and on Auditing for Data Integrity and security of records.

The Guide will contain a Glossary as well as some illustrative appendices for further information.

Margarita Sabater, Member of the ECA Task Force, will present the Draft Version of the ECA Data Integrity Guidance Document during the Lab Data Integrity Conference on 20-21 October 2016 in Vienna, Austria. Every participant will receive a copy of the Draft Document – and is also invited to provide feedback to the Guidance Document.

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Two new FDA Warning Letters for API Manufacturers in China

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Two new FDA Warning Letters for API Manufacturers in China

In June 2016, two API manufacturers in China received a Warning Letter from the FDA. Both companies had major deficiencies regarding data integrity. For instance, manipulations were found in HPLC analyses as well as in GC analyses. You will find more information on the current FDA Warning Letters for Chongqing Lummy and Shanghai Desano here.,15484,Z-QCM_n.html
The Chinese Company Chongqing Lummy Pharmaceutical Co., Ltd. received a Warning Letter from the FDA on June 21, 2016. This Warning Letter referred to both the FDA inspection from March 14-16, 2016 and the response which the API manufacturer had sent to the FDA on March 31, 2016.

It was claimed that Chongqing Lummy Pharmaceuticals had no adequate control in place to prevent data manipulation or deletion. The FDA investigator’s review of the audit trail revealed that an analyst had manipulated the computerized gas chromatography (GC) system to falsify residual solvent results for several API batches.

The analyst had set back the clock of the GC computer to make it appear that the test had been done 7 months earlier. Then he analyzed 5 different injections in order to determine the 12-month value of the long-term stability test. Afterwards, the analyst deleted the original data and only reported the five new results that were conform. The FDA inspection revealed that this procedure of setting back the clock was conducted with at least five other API batches.

During the review of the HPLC system, the FDA inspector found that the HPLC system was configured in a way that analytical results were automatically deleted whenever a test was aborted prior to completion. The review of the audit trail for the Chemstation software indicated that during the analyses of content and impurities, the partial results of aborted tests were automatically deleted from the HPLC system’s records of these analyses. The clock was also set back on the computer for the HPLC analyses in order to retrospectively obtain “conform” results for stability tests.

The company’s response on March 31, 2016 wasn’t satisfactory for the FDA, either. In summary, the FDA writes: “Your response does not indicate how the software upgrades, the SOP revisions or trainings suggested by you can prevent data deletion in the future nor how your quality unit intends to guarantee that the data critical for approval are complete and correct. A response to the FDA is expected within 15 working days. And if you plan to discontinue the delivery of API to the U.S. altogether, FDA requests that you contact CDER’s Drug Shortages Staff immediately.”

Also with the second API manufacturer (Shanghai Desano Chemical Pharmaceutical Co., Ltd.), the data of the laboratory tests were targeted. Here, the main complaint was that laboratory staff performed “unofficial” tests without adequate documentation, justification or investigation:
The original, unofficial analyses were stored in a separate “test folder” and were not part of the official QC data. The inspection revealed that this company had performed about 8,400 of these unofficial chromatographic analyses between 2012 and 2014. According to their internal SOP, all these tests should have been documented. The volume of data in these auxiliary “test folders” suggests that performing unofficial analyses is a common practice at this facility.

You can open the two Warning Letters using these links:
Chongqing Lummy Pharmceutical Co., Ltd.
Shanghai Desano Chemical Pharmaceutical Co., Ltd.

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Is AQL Testing required within the 100% Visual Inspection?

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Is AQL Testing required within the 100% Visual Inspection?
One of the most frequently asked questions is whether an additional testing based on samples is required after the 100% visual inspection of parenterals. The answer is: basically, “yes”.,15484,Z-QCM_n.html

One of the most frequently asked questions is whether an additional AQL testing based on samples is required after the 100% visual inspection of parenterals. The background for that question is the probabilistic nature of visual inspection. It is known that the discovery of defects (like for example particulates) is a matter of detection probability. In other words, visual inspection cannot exclude that defective containers may still be in the batch which hasn’t been sorted out. This applies to manual, semi-automatic and also automatic visual inspection.

The American Pharmacopoeia has reacted to that and has integrated AQL testing in the monograph Visible Particulates in Injections. Here, the value 0.65 has been specifically added for particles testing. This also meets the requirement that injectables have to be essentially free of particles – which is not measurable in this form but with an AQL limit of 0.65. Depending on the batch size and using DIN/ISO tables, it can be determined how large the sample to be extracted has to be after the 100% inspection. It is also set in how many of these samples particles can still be found. Depending on the criticality defined priorly, other defects may required other respective AQL limits.

In Europe, there isn’t any explicit i.e. written requirement for AQL testing (yet). But it is already a state of the art in science and technology. GMP inspectors are also aware that a 100% inspection is “erroneous”, which means that a 100% sorting of defects is not always ensured. The ECA Visual Inspection Interset Group’s Best Practice Guide goes along with the same approach, too. Of course, there are other ways thinkable to optimise the quality of visual inspection, like for example a general second 100% inspection of all batches. This is already practised in many companies; however, only for charges destined to the Japanese market.
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