Will WFI from membrane-based technologies now become an alternative for Europe?

In an EDQM paper published in March 2015 the topic production of WFI by means of membrane-based technologies is discussed again and not excluded any more. Read more about WFI from membrane-based technologies.


In an EDQM paper published in Pharmeuropa in March 2015 the topic production of WFI (water for injections) by means of membrane technologies (reverse osmosis coupled with other suitable techniques) is discussed again and not excluded any more. So far distillation is the only permitted procedure for the production of WFI in Europe. It was already pointed out in the paper on the revision of Annex 1 published in February that alternative procedures for the manufacture of WFI might become possible.

The first part of the new document describes the history of the long lasting discussion of the question whether other procedures than distillation should be allowed for the production of WFI. In the end this led to the creation of a new monograph of highly purified water (HPW). This is water with WFI quality produced by means of membrane-based technologies. But its possible applications were very restricted.

Now it looks as though the Ph. Eur. Water for Pharmaceutical Use (WAT) Working Party has concluded that there is evidence to support a revision of the WFI monograph in the European Pharmacopoeia (0169). As reasons for this change are indicated for example advances in the “non-distillation technology” and improvements in the design of the water-production systems as well as an advanced process control. But it is acknowledged that the design and maintenance of any water-production system plays an important role in ensuring  the security of the produced water. The manufacturer is responsible for compliance with GMP requirements. Presumably, existing guidance documents must be complemented for this by the appropriate stakeholders. Furthermore, quality assurance and monitoring should extend to storage and distribution processes for WFI.

As a result the highly purified water monograph (1927) would be made redundant and be deleted. Furthermore, the inclusion of water for dialysis in the WFI monograph could also be contemplated.

The draft monograph is available on the EDQM webpage for free, after registration. The main change reads:

WFI is produced either by [..destillation, . ].or
by reverse osmosis, which may be single-pass or double-pass, coupled with other suitable techniques such as deionisation and/or ultrafiltration.
Correct operation monitoring and maintenance of the system are essential.

The EDQM already organised a special webinar on April 22nd where this topic has been discussed.

The original document mentioned above discusses the alternative production methods for WFI.


India’s Wockhardt to recall some drugs made in India after U.S. FDA concerns

Indian generic drugmaker Wockhardt Ltd said on Tuesday it would recall some drugs manufactured at its two plants in India before the U.S. Food and Drug Administration (FDA) banned those sites due to quality concerns.

The FDA banned U.S. exports from Wockhardt’s Waluj and Chikalthana plants in central India in 2013, citing manufacturing quality lapses.



Las terroríficas consecuencias de insertar genes de otras especies

La Ciencia y sus Demonios

Uno de los grandes miedos que agitan los pseudoecologistas para incitar a la población a oponerse a los organismos genéticamente modificados es el de las terribles consecuencias que puede acarrear el insertar en una planta o animal genes de otra especie completamente diferente. En una reedición de Frankenstein, se vaticinan las mayores tragedias si esos genes “escapan” al control humano y “contaminan” el prístino banco genético natural.

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New comprehensive GMP Inspection Database available

Just recently a so called “inspection tracker” was launched by Health Canada. Now, the agency offers an additional database which contains 3,821 inspections (per March 2015) which have been performed since 2012 – many of them outside Canada, e.g. in Europe or Asia. The information is available in an online database. The use of the database is very easy and search results are excellent.

By using the database even inspections in progress can be displayed. This is a service no other agency can provide. The database also offers further information about past inspections at the same production site. No further search is necessary because the information about past inspections will be displayed in the search result for a given production site. The rating of the inspection is also provided, and in case of GMP non compliance a detailed and very structured information about the findings is provided. The quality of information about the outcome of the inspection available from the database is outstanding. Again, no other agency worldwide is able not only to list the observations but also link them to the concrete GMP regulation paragraph in a structured and numbered table.

The database also provides information about past and present non-compliance situations. However, it also shows when a company is currently licensed by Health Canada, as the company possibly improved its GMP status and was licensed again.

The database allows three different options to search for information. The first option contains 1,301 Inspections (per March 2015) from the past three years performed in Canada. A second option allows to access the non-compliance information. Currently 52 production sites with non compliance statements are listed in the database (some of the sites received their license again after re-inspection). The third option offers access to 2,520 inspections (per March 2015) performed outside of Canada.

To access the database please visit Health Canada Drug & Health product Inspections Webpage


The “Industry Coalition” gives practical advice for the control of elemental impurities in active substances and excipients

The requirements of the “Guideline for Elemental Impurities ICH Q3D” published in December of last year mean a considerable expense for the affected pharmaceutical companies and drug manufacturers in terms of laboratory and personnel upgrading (see also our news about “ICH Q3D – Elemental Impurities” of 07 January 2015). In addition, the deadlines for the implementation of this guideline are quite tight. (June 2016 for newly approved drugs and December 2017 for already approved drugs, see our news “CHMP adopts ICH Q3D Guideline as “Scientific Guideline” of 21 January 2015).

In the March issue of “Pharmaceutical Technology Europe”, an article of the “Industry Coalition” has been published with the title “Implementation of ICH Q3D Elemental Impurities Guideline: Challenges and Opportunities“, which is intended to support the efffected companies with a number of pragmatic pieces of advice in the implementation of these requirements.

The “Industry Coalition” (exact name: “Coalition for Rational Implementation of Elemental Impurities Requirements”) is a consortium of economic/industrial associations (members include IPEC Europe, IPEC Americas, The Generic Pharmaceutical Association GPhA, etc.) and has been in existence since 2011. The aim of the coalition is to provide information regarding elemental impurities. To this end, the Coalition has developed a standardised procedure (standardised information request) according to which specific information can be requested through the use of a form. More information about the “Industry Coalition”, their goals and projects can be found in a Position Paper which appeared in “Pharmaceutical Technology Europe” in November 2012.

The Guideline ICH Q3D calls upon drug manufacturer to conduct a risk assessment as part of a strategy for the control of element impurities, but without specifying which aspects need to be considered in such an assessment. Here, the article of the “Industry Coalition” provides helpful hints; it is described how, for example, production equipment (various types of steel), processing aids (activated carbon, silica gel, etc.), inorganic reagents, solvents, packaging materials and closure systems are to be included in the risk assessment. A detailed section is dedicated to the subject of excipients, regarding which the assessment of risks is often particularly difficult in terms of element impurities, due to the unclear origin or the complex composition of the excipients.

The approaches described by the “Coalition” may be useful for many companies in their efforts to meet the requirements of the Guideline ICH Q3D. In this context, the document which has recently been published by the EMA  entitled “Elemental impurities in marketed products. Recommendations for implementation” should also be considered……………..http://www.gmp-compliance.org/enews_04794_The-%22Industry-Coalition%22-gives-practical-advice-for-the-control-of-elemental-impurities-in-active-substances-and-excipients_9343,9263,9300,S-QSB_n.html

Data Integrity – Again Import Alert issued for Indian company IPCA

Data Integrity – Again Import Alert issued for Indian company IPCA…http://www.gmp-compliance.org/enews_04789_Data-Integrity—Again-Import-Alert-issued-for-Indian-company-IPCA_9193,S-QSB_n.html

Data Integrity has become one of the most important GMP compliance issues in past two years. This has enormous consequences for the concerned companies but also for companies and authorities in EU and US. It was the US FDA that has first experienced huge data integrity problems in companies worldwide. Many sites in India have been found to violate GMP requirements by Data Integrity issues. Tests have been repeated and original data have been deleted. This is called “testing into compliance”. At the Webpage of the US FDA IPCA products are listed which are impacted by the Import Alert. Two facilities from IPCA have been found to be out of GMP compliance: One in Pithampur (Madhya Pradesh) and one in Piparia (Silvassa) (see also report by FiercePharma).

Products manufactured at those facilities might cause high risks to patients. The quality of the products can not be specified because the original test data were simply deleted. The company IPCA was already known for not meeting the GMP requirements. Already in July 2014 IPCA halts US shipment from the Ratlam plant after FDA found massive GMP violations. As a consequence the Canadian Authority (Health Canada) has banned a huge list of APIs and medicinal products from their market as well. Now they have informed the Bombay Stock Exchange about their problems (see message regarding Import Alert issues by IPCA)

But what are the consequences for companies and authorities in Europe and the US? Authorities might be asked why the same facilities that have been found to be involved in the falsification of data are still allowed to supply to EU patients. For example IPCA is still listed with a GMP certificate for the concerned facilities in EudraGMDP. And EU and US companies need to check very carefully which supplier, partners and own sites they have in India. Quite a few companies have been found to delete data and to perform testing into compliance. FDA has started to check whether companies have checked their suppliers for data integrity. The MHRA has put this on the agenda for their inspections as well.

Ozonization of Pharmaceutical Water and the Biocidal Products Regulation

New Drug Approvals

With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this directive. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. The ozone registration group is active for this purpose. Read more about the Ozonization of Pharmaceutical Water and the Biocidal Products Regulation.


With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this regulation. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. We already reported about the impact of the new Biocidal Products Regulation – please see the GMP News “Pharmaceutical Water: Uncertainty caused by the New Biocidal Products Regulation” from 21 May 2014.

Admission will…

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New EU GMP Annex 15 Revision published – Valid as of 1 October 2015



In February 2014 the draft for the revision of Annex 15 was published. Compared with the currently valid version the changes were partly significant. Now the draft was published as final document and will be valid as of 1 October 2015. Read more about the Changes in Annex 15.


In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 “Revision of the EU GMP Annex 15 for Qualification and Validation published“). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 “Detailed Analysis of Annex 15 Draft“. Now the draft was published as final document and will be valid as of 1 October 2015.

What will change? Following you will find an overview about the changes.

With 16 pages the document is much more comprehensive than the current version (11 pages). In the section “principles” it is stated that the new EU GMP Annex 15 may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II”

Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process, whether with regard to equipment and the process validation itself. A special emphasis is on risk management which is mentioned in several sections in the guideline instead of being mentioned in one section only on risk assessment.

The new Annex 15 now specifically excludes a retrospective validation.

Validation Master Plan
The content of the validation master plan (VMP) has been extended. Deviation management is also supposed to be described in the VMP in the future, just as well as the standards for the development of acceptance criteria and the organisational structure. Compared to the draft version the mention of an “ongoing validation strategy” has been deleted. The request for naming the resources has also been omitted compared to the draft.

The possibility to combine qualification documents (e.g. IQ and OQ as IOQ) is explicitly mentioned. It is also foreseen to include manufacturer documents. Fortunately there is the possibility of conditional releases in the area of qualification. The final document contains a requirement to establish user requirements and/or functional specifications as a starting point of a qualification. The DQ is now the second step in a qualification. Additional new requirements are the Factory Acceptance Test (FAT) and the Site Acceptance Test (SAT). Especially for equipment with new or complex technology a FAT “may” be conducted. Compared to the draft this is a less strict requirement. In the draft document it was stated that a FAT “should” be conducted. If appropriate and assessed, tests and documentation reviews as part of the FAT can be taken over in other steps without repeating them in the IQ/OQ. This is a very helpful definition.

With regard to the PQ it is now also explicitly mentioned that (in certain cases) it can be combined with the OQ or the process validation. In difference to the draft it is stated that IQ, OQ and PQ “should” be conducted.

The chapter “Requalification” is new. Unfortunately the sub-chapter on established (in-use) equipment qualification has been completely omitted.
Process Validation
The options with regard to process validation have been extended. The previous “traditional” approach is still mentioned as a possibility, though – also with the determination of 3 validation batches. For a 3 batch validation further data from following batches may be necessary according to an “ongoing process verification”. The possibility of a “continuous process verification” as described in ICH Q8, and a hybrid approach as a mix of the before mentioned two approaches is new. This is a clear difference to the US FDA Process Validation Guidance where only one approach is mentioned. According to the final EU GMP Annex 15 a “bracketing” approach can be used with respect to the number of runs, strength, batch size, packaging sizes and types. This is already known from the US.

As part of the “ongoing process verification” the product quality should be monitored during the product life cycle to show that the “state of control” is fulfilled and that trends are assessed. This is also known as “Continued Process Verification” from the US. The “ongoing process verification” should be based and reported according to a protocol or equivalent documents, latter is new compared to the draft. Completely omitted has been the subject of a (regular) revalidation.

The chapters “Transport Verification”, “Packaging Validation” and “Qualification of Utilities” as well as a separate chapter on “Validation of Analytical Methods” are new.  Compared to the draft the new final document now addresses also the qualification of equipment for secondary packaging.

Cleaning Validation
The chapter Cleaning Validation comprises clear changes. The number of subitems is more than double now. Fortunately it is possible now to group equipment if this grouping is justified accordingly. The acceptance criterion “visibly clean” as single acceptance criterion is designated as not acceptable. Limits for the carryover of contaminations are supposed to be based on a toxicological evaluation. There is a reference to the EMA Guideline on Shared Facilities (see GMP News from 21 November 2014 “Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits (PDEs)“. The so far common acceptance criteria 1/1000-Dose or 10 ppm are not mentioned. As part of the cleaning validation “dirty und clean-hold times” should be defined. The request from the draft to use the last rinse water as a sample in the application of rinsing methods has been omitted. Recovery rates should be determined. Interestingly the number of validation runs is supposed to be determined risk based. When producing clinical trial samples a cleaning verification could replace a cleaning validation.

In the chapter Change Control it is defined that an efficiency control is supposed to follow a change. This is an adaption to chapter 1, part I of the EU GMP Guide.

The glossary contains new terms.

The revision is quite comprehensive. Influences from the ICH Guides ICH Q8, Q9 and Q10 can be clearly noticed. This makes the document more modern, and it is more adapted to the current state of science and technology. The addressing of API manufacturer is somewhat irritating. Although the new Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs. But how is that supposed to work?

The statement that Process Validation is a life cycle is comparable to the FDA view.

The clear focus on user requirements in the area of qualification will also have an impact on equipment suppliers. Process validation will become a difficult task in the future. With 3 different approaches there are clear differences to the US. However, the ongoing process verification means additional effort and is now comparable to the US requirements.

Transport verification, the qualification of utilities as well as the validation of analytical methods are not new in the GMP enviroment. However, the topic packaging validation was not the main focus so far. This probably means additional effort for some companies.

The new Annex will result in considerable changes in the area of cleaning validation. A lot has fortunately been adapted to the current state of technology. However, the strong focus on toxicological evaluations as acceptance criteria with regard to existing products will certainly cause uncertainties.

Altogether there are plenty of new requirements which, however, partly only show the state of technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the FDA Guideline on process validation would have been desirable.

Please find the new EU GMP Annex 15 on the EU Commission Webpage

The new EU GMP Annex 15 will be covered at two ECA events. On 22/23 April the ECA offers the seminar “The new FDA/EU Approach to Process Validation” in Hamburg. And, at the 6th European GMP Conference on 9/10 June in Heidelberg the EU GMP Annex and the consequences will be discussed in a dedicated session.

Gmp Guideline Eu Gmp Annex 15 Qualification And Validation

Gmp guideline eu gmp annex 15: qualification and validation, Eu gmp annex 15: qualification and validation: internet: http://www.gmp-compliance.org/guidemgr/files/2-8-4-15–v4an15.pdf: origin/publisher: european commission. Eu gmp guide – annex 15 qualification & validation draft, White paper eu gmp guide-annex 15 qualification & validation draft released © 2014 pharmout. this document has been prepared solely for the use of pharmout and its. Guideline: eu gmp annex 15: qualification and validation, Regelwerke zu good manufacturing practices ändern sich. mit dem gmp-navigator bleiben sie auf dem laufenden. gmp-navigator.Definition of DQ (EU GMP Guideline, Annex 15) - Design qualification

New draft gmp guideline – european commission, 4 qualification and validation principle this annex describes the principles of qualification and validation which are applicable to the facilities, equipment. European medicines agency – gmp/gdp compliance – questions, European union (eu) gmp guide part i: basic requirements for medicinal products: chapter 3: equipment. back to top. 1. should metal detectors be used routinely in. Gmp news – good manufacturing practices – gmp newsletter, Gmp news about eu, ema, europe, us fda, pharmaceutical quality, ich, who, pic/s..

Definition of DQ (EU GMP Guideline, Annex 15) - Design qualification
Definition of DQ (EU GMP Guideline, Annex 15) – Design qualification

Click here to get More Info About Gmp Guideline Eu Gmp Annex 15 Qualification And Validation


Overview about API manufacturing for the European market



EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Please read more about the API registrations in EudraGMDP.


EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Although the database is still not complete (not all competent authorities in Europe have established a system to make sure that all registration data will be entered into EudraGMDP in a timely manner) the current information is already very interesting.

Currently (as per 19 March 2015) the database counts 3.275 API manufacturing sites, importers or distributors located outside Europe. On the other side 936 API manufacturing sites, importers or distributors are located in EEA countries (EU Member states plus Norway, Liechtenstein and Iceland). According to the database India counts for 1.473 companies and China for 1102 companies. The USA only counts for 198 and Switzerland for 71 companies. Within the EEA the United Kingdom counts 138 countries while Italy counts for 71and Spain for 192. Still work is needed to put all information into the database as France does not have a single entry and Germany only 3.

But the database is a good source to find some basic information about API manufacturers, importers and distributors. Each company registration file is available and allows to check the date of issue of the registration and the products concerned. However, it must be stated that a registration does not mean that an inspection took place. A registration will be granted also without a prior inspection at the company.

Source: API Registration in EudraGMDP


Novel Approaches to Drug Development – 2015 Eppic Annual Conference

Darshana Varia Nadkarni's Blog

Drug development panel discussed how the technological advancements in Big Data, Machine Learning and Cloud Computing, when paired with focus on combination therapies that include for instance, anti cancer and immuno oncology agents, or paired with next gen sequencing technologies, and advanced companion diagnostics, with relentless focus on patient outcomes, may open new frontiers in cost effective drug development.

Drug development panel was moderated by Dr. Suneel Gupta, Chief Scientific Officer at Impax Pharmaceuticals.  Gupta has over 25 years experience in pharmaceutical R&D, specifically around drug delivery technologies.  Gupta shared the story of how Impax launched RYTARY, an extended-release oral capsule formulation drug, for the treatment of Parkinson’s disease, and took it in a span of 3.5 years, with $100M, from benchmark to launch.  This is Impax’s first branded drug internally developed and approved for commercialization and it was achieved with “relentless execution”, said Gupta.  Gupta’s advice to…

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