Stability Testing related News – Vol.5

◆  Selection and justification of starting materials: new Questions and Answers to ICH Q11 published (07-Dec-16 ECA)

The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.

On 30 November 2016 the ICH published a Questions and Answers document “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)” which was developed by the Q11 Implementation Working Group. This document aims at addressing the most important ambiguities with respect to starting materials and at promoting a harmonised approach for their selection and justification as well as the information that should be provided in marketing authorisation applications and/or Drug Master Files.

In the following some examples of questions and answers from this document:


ICH Q11 states that “A starting material is incorporated as a significant structural fragment into the structure of the drug substance.” Why then are intermediates used late in the synthesis, which clearly contain significant structural fragments, often not acceptable as starting materials?


The selection principle about “significant structural fragment” has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance. However, as stated in ICH Q11, the principle is intended to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. … The presence of a “significant structural fragment” should not be the sole basis for of starting material selection. Starting materials justified solely on the basis that they are a “significant structural fragment” probably will not be accepted as starting materials by regulatory authorities, as the other principles for the appropriate selection of a proposed starting material also require consideration.


Do the ICH Q11 general principles for selection of starting materials apply to processes where multiple chemical transformations are run without isolation of intermediates?


Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.

The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.


Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?


Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process … . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.

ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.



◆  End of TTIP? What about the MRA with FDA? (21-Dec-16 ECA)

A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections is part of the Transatlantic Trade and Investment Partnership (TTIP). The idea was to have the agreement signed already in January 2017. This was noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections, by January 2017, is under consideration.”

But currently, with the election of Donald Trump as the next president of the USA, TTIP will have a rather low chance for implementation. The rejection of free trade agreements was a central message during Trumps’ election campaign. The conversations about TTIP have currently entered a kind of rest phase.

Nevertheless the MRA was also discussed at the 84th GMP/GDP Inspectors Working Group with Interested Parties at the European Medicines Agency (EMA) on 23 November 2016. Like every year, the European QP Association was also invited to attend this meeting. At the last meeting, EQPA was represented by Dr Afshin Hosseiny, who is also Co-Chairman of the ECA Executive Board. During the meeting it was pointed that EU is still aiming to sign off the agreement, although there was some concern that the new administration may decide to change it or cancel altogether. If signed, there will be a transition period for the implementation. US FDA still wants to satisfy itself on each member state. “It is not clear how this is going to be achieved, but import testing will be part of the negotiations.” Dr Hosseiny says. This could possibly mean that not all member states are approved at the same time, which is not really going to fit with the EU philosophy. It is worth to mention that the agreement will not include import testing; so any imported product from USA has to be retested in EU before release. “It is a goal to include import testing, but it is not clear when that can be implemented”.

It is important to mention in this context that there has been an “Agreement on Mutual Recognition between the European Community and the United States of America” signed on 4.2.1999, with a chapter 6 on “Pharmaceutical Good Manufacturing Practices (GMPs)”. This MRA included a three-year transition period in which the US FDA wanted to satisfy itself on each Member State’s inspection practice. After performing several mutual inspections, the FDA made proposal to have the MRA limited to only some Member States. This was not acceptable for the EU. So the MRA never became effective.

And what does FDA think? In a presentation given by Janet Woodcock (Director CDER) at the FDA/CMS Summit on 14 December in Washington, she said that “Negotiating, with Global Operations Office, a Mutual Reliance Agreement with Europe on facility GMP inspections” is still on the programme.



◆  Revised USP Chapter <1058> on Analytical Instrument Qualification (18-Jan-17 ECA)

In the Pharmacopeial Forum No 42(3), the USP has published the draft for the revised General Chapter “Analytical Instrument Qualification”. This draft takes into consideration the comments sent to the USP. Besides, some formal aspects have also been modified to bring this chapter into line with USP’s today usual phrasing.

There are many possibilities to demonstrate that an instrument is qualified and under control – amongst others with qualification, calibration, validation and maintenance. An integrated approach – based upon a risk assessment – is recommended to demonstrate that an instrument is suitable for its intended purpose. Here, data integrity and security are essential aspects.

This approach isn’t a unique process but the result of different activities over the lifecycle of an instrument. This way, Design Qualification (DG) can be performed both by the instrument manufacturer or the user in the lab.

If there is a remaining instrument in the lab which hasn’t been qualified before or can’t be qualified according to the currently valid standards, the existing documents should be compared and evaluated by means of a risk assessment to determine the best approach.

Furthermore, it is stated in the revised draft that Operational Qualification (OQ) relies on the fixed parameters of an instrument such as length, height, weight or pressure. Such fixed parameters which cannot change over the lifecycle of an instrument do not need to be retested later.

If an instrument is moved to another location, an assessment should be performed to decide whether and what qualification activities have to be repeated.

The classification in three groups A, B and C depending on the complexity of the instruments has proven to be sound and will be retained.



◆  European Authority’s Inspection Findings in the Area Validation/Qualification (01-Feb-17 ECA)

The US American Food and Drug Administration (FDA) has long been publishing inspection results in so-called Warning Letters. Those letters are freely available on the Internet. Since a few years now, major violations of GMP have been published in a European inspection database. The British Regulatory Authority (MHRA) does this in a much more detailed way. Read the following examples published by the MHRA on the topic area validation/qualification from 2015.

In the top 10 of MHRA’s inspection deficiencies 2015, the topic validation occupies rank 8. However, no critical deficiency was found. Most “major” deficiencies concerned the validation report and changes to the validation plans.

Regarding the topic qualification, the MHRA presents the following exemplary deficiencies:

  • Lack of design phase (DQ, URS) for new equipment
  • Qualification documents provided by equipment suppliers were not integrated into the company’s pharmaceutical quality system to ensure appropriate review.
  • The use of suppliers’ documentation for the qualification was criticised a second time: the OQ protocol for an HVAC system obtained from a supplier hadn’t been compared and checked with the company’s requirements prior to its approval.
  • One heat tunnel equipment hadn’t been fully qualified in the OQ.

With regard to the topic cleaning validation, the MHRA criticised that:

  • The effective removal of organic compounds couldn’t be assured.
  • The effectiveness of sprayballs used for vessel cleaning hadn’t been demonstrated nor controlled.
  • The permitted limits for carryover of organic molecules had neither been set nor risk assessed.
  • No swab samples had been taken – in particular from difficult to clean areas where other methods or determining residues may not be effective.
  • There was no scientific rationale to support the selection of products used for the cleaning validation.

Concerning process validation, the MHRA gave the following examples deficiencies:

  • The performance and process validation activities didn’t include any assessment of all critical parameters (e.g. tablet dimensions and embossing).
  • Not every aspect of manufacturing was covered by process validation (e.g. the use of small coating pans as opposed to the validated automated system).
  • Validation batches were released before process qualification had been completed.

It is interesting to note that the MHRA criticised twice that the companies inspected had no formal processes for implementing changes in the GMP regulations. Annex 15 – which became applicable as revised version in October 2015 – had been explicitly mentioned once.

You can find the complete MHRA’s report on GMDP findings on their website.


If you have any questions, feel free to ask us

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