regulatory – Page 5 – All About Drugs

Revision of the general Chapter on Pharmaceutical Water in the US Pharmacopoeia

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Jun 162016

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes.

http://www.gmp-compliance.org/enews_05410_Revision-of-the-general-Chapter-on-Pharmaceutical-Water-in-the-US-Pharmacopoeia_15160,15266,15221,15612,Z-PEM_n.html

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes. The first draft version had already been published in September 2015 in the USP Pharmacopeial Forum 41(5).

First of all: there are no new or revised specifications of individual test parameters or new requirements. But the chapter has been revised structurally to ensure better readability. In addition there are now also details regarding feed water as well as for the validation and on action and warning limits. With a chapter number greater than 1000 the Chapter <1231> is not binding, but has a recommending character. The recommended temperature for hot sanitising was changed. So far temperatures of 80 ° C and greater were recommended. Now these are 65-80 ° C. Regarding the action and warning limits the USP now comprises proposals how these can be set 2 – and 3-stepped and which rationale can be used for the limit-setting. Further, the revised chapter now also provides assistance for organising sampling plans for the validation and operational phases.

The revised version of the Chapter <1231> will become effective in December 2016 and can be found in the 2nd supplement to the USP39 NF34.

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Final WHO Guidance Document on Good Data and Record Management Practices

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Jun 162016

The WHO has just released the the final version of the important guideline “Good Data and Record Management Practices“.

http://www.gmp-compliance.org/enews_05418_Final-WHO-Guidance-Document-on-Good-Data-and-Record-Management-Practices_15488,15637,Z-COVM_n.html

We recently informed you about the WHO Draft Guidance on Good Data and Record Management Practices. Now, the WHO has just released the the final version of this important guideline “Good Data and Record Management Practices”.

The final version is sectioned rather similar to the draft version:

– Introduction
– Aims and objectives of this guidance
– Glossary
– Principles
– Quality risk management to ensure good data management
– Management governance and quality audits
– Contracted organizations, suppliers and service providers
– Training in good data and record management
– Good documentation practices
– Designing and validation systems to assure data quality and reliability
– Managing data and records throughout the data lifecycle
– Addressing data reliability issues
– References and further reading

Although the individual chapters were kept rather unchained the content of these chapters was updated throughout the whole document.

For instance the term “good documentation practices” has now been expanded to “good data and record management practices” and is defined as follows in the glossary:

“The totality of organized measures that should be in place to collectively and individually ensure that data and records are secure, attributable, legible, traceable, permanent, contemporaneously recorded, original and accurate and that if not robustly implemented can impact on data reliability and completeness and undermine the robustness of decision-making based upon those data records.”

Some of the former content has been put into Appendix 1 now: Here you can find expectations and examples of special risk management considerations for the implementation of ALCOA (-plus) principles in paper-based and electronic systems. The tables in this appendix provide further guidance on the implementation of the general ALCOA requirements. In addition, examples of special risk management considerations as well as several illustrative examples are provided of how these measures are typically implemented.

However, these examples should not be taken as setting new normative requirements.

For further information please see the final WHO Guidance on Good Data and Record Management Practices.

//////Final , WHO Guidance Document, Good Data and Record Management Practices

WHO defines Requirements on Zones E and F

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Jun 092016

In May, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. It also contains for the first time a definition for microbial requirements with regard to the zones E and F. Read more about the ventilation sytems recommendations.

http://www.gmp-compliance.org/enews_05367_WHO-defines-Requirements-on-Zones-E-and-F_15221,15231,15612,15266,Z-PEM_n.html

In May 2016, the WHO published a draft guideline which describes the recommendations for ventilation systems used in the manufacture of non-sterile dosage forms. From a technical point of view, the guideline is very interesting and includes a detail which may be overlooked: it contains – as first international GMP guideline – a proposal for the definition of microbiological requirements concerning the zones E and F. So far, the approach to extend the zoning via the zones A-D defined in Annex 1 to the zones E and F and thus define microbial limits had only been available in an Aide Memoire of the ZLG (in German language). Now for the first time, this information is available in an international guide. As there are far less regulations in the area of non-sterile medicinal products than in sterile manufacturing, the proposal should be of great interest.

Access the draft Supplementary Guideline on GMPs for Heating, Ventilation and Air-Conditioning Systems for non-sterile Dosage Forms on the WHO webpage to find more detailed information. The deadline for comments ends on 12 July 2016.

////////WHO, microbial requirements, zones E, F

Results of a Survey on ICH Q3D “Elemental Impurities”

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Jun 022016

For most companies manufacturing APIs and pharmaceutical products, the implementation of ICH Q3D has a serious impact – as shown in a survey recently carried out by the ECA. Read more about the issues encountered by many companies regarding the assessment and control of elemental impurities and the kind of support they wish.

SEE

http://www.gmp-compliance.org/enews_05395_Results-of-a-Survey-on-ICH-Q3D-%22Elemental-Impurities%22_15499,15332,S-AYL_n.html

One and a half years after the official entry into force of the ICH Q3D Guideline for “Elemental Impurities” and several supporting documents from the ICH (e.g. “Training Package: Modules 0-7“) a number of questions as regards implementation remain.

In a survey recently performed by the ECA, questions were posed about the issues relating to the fulfilling of the requirements laid down in ICH Q3D. The feedback from almost 80 participants from medium and large pharmaceutical companies and API manufacturers located in Germany and other EU Member States shows remarkable results which harsh light on the aspects companies have to struggle against with regard to the implementation of the guideline. Please find an extract of this survey below:

How strong is the impact of the ICH 3D Guideline on your Company?

For more than half of the respondents, ICH Q3D has a strong impact on the company.

Where do you see the main problems for implementation of ICH Q3D?

For most companies, not only the establishment of safety assessment of potential elemental impurities is seen as problematic but also the analytical procedures for elemental impurities testing required for proving elemental impurities as well as the application of the requirements of ICH Q3D to old products.

Application of ICH Q3D to existing products is not expected until 36 months after publication. How do you judge this deadline?

Whereas a quarter of the companies surveyed judge the time for application of ICH Q3D to existing products as too short, half of them consider it nevertheless feasible – with great effort though.

The following question clearly shows what support companies especially wish with regard to the problematic:

What kind of information would you like to receive from ECA in case that ECA would establish an Interest Group?

Examples for risk assessment for elemental impurities would be highly appreciated; besides, also procedure descriptions i.e. SOPs on how to handle the establishment of risk assessment as well as conferences, workshops or forum on that topic have been assessed as very useful.

///////Results, Survey, ICH Q3D, Elemental Impurities

EDQM’s new Guideline on Electronic Submissions for CEP Applications

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Jun 022016

EDQM’s new Guideline on Electronic Submissions for CEP Applications

As of today (June, 1st 2016), the EDQM doesn’t accept any CEP application in paper format. Read more here about the structure of the electronic submission of an application for a Certificate of Suitability and the errors to avoid.

SEE

http://www.gmp-compliance.org/enews_05380_EDQM-s-new-Guideline-on-Electronic-Submissions-for-CEP-Applications_15429,15332,S-WKS_n.html

The EDQM has recently published a document entitled “Guidance for electronic submissions for Certificates of Suitability (CEP) applications” (PA/PH/CEP (09) 108, 3R) in which the authority describes the requirements to be considered for the submission of an application for a CEP. Let us give you the most important message straight away: the EDQM now only accepts CEP applications in the electronic format since June 1st 2016.

Only the following formats are authorised within an application procedure: PDF, NeeS (non-eCTD electronic submission), VNeeS (the respective application format for veterinary purposes) and eCTD. A change of format during an ongoing application procedure is allowed whereas coming back to the original format isn’t. Basically, the EDQM recommends the use of the eCTD with an exception though: CEP applications for the TSE risk of an API have to be submitted in the PDF format.

The guideline extensively describes how a CEP application should look like with regard to its content and structure. This is illustrated by 5 annexes which present the structure and level of granularity (degree of division in subchapters) of the different formats. The sixth annex (“Main issues which may lead to blocking a submission for its format and causing delays”) lists the problems which may lead to delays in the application procedure with the respective reasons and solutions presented in a table. For example, typical errors in the electronic submission are on the one hand those which complicate the navigation through the application (inappropriate level of granularity, annexes not incorporated in the CTD structure, incorrect designation of PDF bookmarks, etc.) and on the other hand those which disrupt the lifecycle of the application in the eCTD format (wrong sequence of the chapters, incorrect attributes, e.g. “New” instead of “Replace” when replacing a leaf).

Generally, the standards applicable for the electronic submission of an application for a marketing authorisation of medicinal products must also be fulfilled in a CEP application. The “Electronic Standards for the Transfer of Regulatory Information” (ESTRI) have been elaborated by ICH’s M2 Expert Working Group and are available on a separate website: the ESTRI webpage.

Now, the electronic submission of a CEP application can be done via the “Common European Submission Platform” (CESP) of the EDQM. First, a registration on the “Common European Submission Portal” is necessary. If it’s not possible, there are other alternatives: secured drop-box (the EDQM provides the access data on request), CD-ROM, DVD and USB stick. Password protection or encodings must be removed first.

//////////// EDQM, Guideline, Electronic Submissions, CEP Applications

Crisil rings warning bell for pharma on US slowdown

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May 262016

Companies like Dr. Reddy’s Laboratories and Sun Pharma derive close to 60% of their revenue from exports to the US. Lupin too, gets 45% of its revenue from generic formulation sales to the US, while others like Cadila Healthcare, Torrent Pharma ……………

Crisil rings warning bell for pharma on US slowdown

////Crisil, warning bell, pharma, US slowdown

EU GMP Annex 1 Revision 2016 – what does the pharmaceutical industry expect?

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May 262016

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech at the Pharma Congress 2016 about the revision of Annex 1 of the EU GMP Guide. Read here what the pharmaceutical industry expects form the new Annex 1.

http://www.gmp-compliance.org/enews_05326_EU-GMP-Annex-1-Revision-2016—what-does-the-pharmaceutical-industry-expect_15160,15266,15265,15432,Z-PEM_n.html

Europe’s biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech about the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice. The first version dates already back to the year 1972. Dr Haefele stated that there had already been five revisions since this time but no fundamental review. This means the time has come to revise this fundamental document on the regulation of sterile manufacture in Europe.

Dr Haefele demonstrated the need for action on one hand by a comparison with the FDA Aseptic Guide and on the other hand by means of his own commenting. Friedrich Haefele said that priority should be given to harmonisation. He basically believes that Annex 1 should remain reserved for sterile parenteral products and that other sterile products or active pharmaceutical ingredients should be regulated in other documents or in specific annexes. He also wants a separation between aseptically manufactured and terminally sterilised products in the new Annex 1.

He considers DIN ISO 14644-1 to be a central document that is used for the classification of clean rooms in the European Guideline but also in the US Guide. Dr Haefele is not bothered by the fact that the limit for 5 µm particles has been deleted from the grade ISO 5 (ISO 4.8). According to him it should also be deleted from the European requirements. Deviations in the case of 0.5 and 5 µm particles occur essentially in parallel so that it should be possible to renounce to the limit for 5 µm particles.

Dr Haefele also proposed a simplification for the microbiological environmental monitoring. Settle plates as well as microbial air sampling are required in Europe at the moment. According to Dr Haefele only the microbial air sampling should be compulsory whereas the use of settle plates should be optional or additional. The use of average values in the microbiological monitoring in the clean room should be dismissed. With the use of isolators with validated decontamination cycles the microbiological monitoring could be reduced to the essential pursuant to ICH Q9 Quality Risk Management.

In contrast to the FDA Aseptic Guide the European Annex 1 contains requirements concerning the crimping process as well as a differentiation between aseptic and clean processes. For the latter Dr Haefele wants a clear definition of “Grade A Air Supply” that should be used for protection during the process according to Annex 1. Dr Haefele stated that the industry has its opinion concerning this but that it should also be recorded in the relevant official document. By this he meant the use of air filtered according to the requirements of grade A without considering the microbiological requirements.

There are important differences between Annex 1 and the Aseptic Guide in the area of sterilisation. The US document contains no indications for a terminal product sterilisation. It is contained in the EU document. Dr Haefele proposes to limit the requirement for a sterilisation with pure steam primariliy to the terminal product sterilisation and to also allow other methods e.g. sterilisation with ethylene oxide for example for so-called ready-to-use materials.

He sees further potential for improvement concerning the topic sterile filtration. He considers that the integrity testing after sterilisation immediately before filling can be omitted since the data of the filter validation and the integrity testing after filling give adequate security. To renounce to the obligatory integrity testing after sterilisation and before use, reduces the complexity of the aseptic set-up and when constructing facilities.

A further difference concerns the quality oversight. In Europe there is no requirement that the quality assurance (physically) must take place on-site during aseptic processes. But the Aseptic Guide requires a QC oversight and here, especially the media fill is mentioned. Dr Haefele invoked a harmonisation of the requirements, in order to strengthen the European philosophy, however. Quality assurance is a system and not an organisation. Mr. Haefele proposed a further change concerning the media fill in isolators. Here, interventions are carried out from the outside when carrying gloves. This means that they are “person-neutral”. The requirement that the qualification of interventions during the media fill has to be done person-specific should therefore be omitted for media fills in isolators.

As concerns the topic disinfection Mr. Haefele would prefer the admission of hydrogen peroxide for the decontamination of surfaces in isolators and material locks as well as the dispensation with the mandatory rotation when using disinfectants.
A further topic in Annex 1 is the monitoring of the integrity of containers containing sterile medicinal products. At the moment, the Annex requires a 100% integrity testing only for containers closed by fusion (glass ampoules and BFS containers). Dr Haefele would prefer more openness up to suitable controls for all packaging systems or pharmaceutical dosage forms.

Finally, he reaffirmed the use of modern barrier techniques for the aseptic manufacture as state-of-the-art and repeated his wish for a harmonisation of the requirements for sterile and aseptically produced medicinal products. MRA, mutual recognition agreements, could reduce the number of regulatory inspections at the companies.

Currently, the publication of the draft of the new EU GMP Annex 1 is planned for autumn 2016.

Source: Pharma Kongress 2016 (companies who wish to book a booth in 2017 can register here)
/////Dr Friedrich Haefele, Vice President, Fill & Finish Biopharma, Boehringer Ingelheim, EU GMP Annex 1 Revision 2016, pharmaceutical industry,

WHO issues revised Guideline on HVAC Systems

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May 262016

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.

http://www.gmp-compliance.org/enews_05358_WHO-issues-revised-Guideline-on-HVAC-Systems_15160,15221,15661,15612,Z-PEM_n.html

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of highly potent materials the WHO refers to their Guideline TRS 961, Annex 3.

The biggest changes comprise:

The chapter “Premises” was moved to the front to emphasize its importance. The chapter now further comprises some sample layouts
The section “Commissioning, Qualification and Validation” was revised to match it with the WHO Guideline TRS 937, Annex 4 (Supplementary guidelines on good manufacturing practices: validation)
The part “Maintenance” was removed from the part “Commissioning, Qualification and Validation” and is now a separte chapter
In addition a number of comments were added, graphs revised, and the overall readability was improved

Due to the many references and the numerous and improved illustrations the document is a good source for the (exemplary) requirements in the manufacture of solid and non-sterile dosage forms.

To find out more please visit the WHO website where you will find the draft document SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS. The deadline for comments is the 12 July 2016. The results are expected to be discussed during the 51st WHO expert committee meeting in October.

///////////WHO, revised Guideline, HVAC Systems

ICH M7

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May 192016

ICH M7

Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.(5) This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a series of articles within the special edition.

A tabulated summary of the special edition is described in Table 1.

Table 1

subject	highlights	authors
Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?	A survey of over 300 synthetic publications in OPR&D over a 10 year period clearly demonstrated that the synthesis of synthetic APIs was untenable without the use reactive, potentially mutagenic reagents/intermediates. That the principle of avoidance was fundamentally flawed	Elder, D. P.; Teasdale, A.(6)
Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products	The paper outlines a strategy for the systematic assessment of the risk posed by mutagenic degradants, describing how this relates to stress testing and long-term stability studies. Within this it seeks to define appropriate thresholds for identification directly related to the extent of degradation	Kleinman, M. H.; Teasdale, A.; Baertschi, S. W. et al.(7)
Assessing the Risk of Potential Genotoxic Degradation Products in a Small Molecule Kinase Inhibitor Drug Substance and Drug Product	The degradation profile resulting from stress testing of galunisertib is described, focusing on formation of two N-oxides, examining the site of oxidation and the relevance of the pathway under typical storage conditions.	Strege, M. A.; Osborne, L. M.; Hetrick, E. M. et al.(8)
Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions	Provides a comprehensive review of the existing evidence relating to sulfonate esters, examining the comprehensive mechanistic and kinetic studies and safety data. It also examines the current regulatory approaches and how this appears misaligned with the data.	Snodin, D.; Teasdale, A.(9)
Mutagenic Impurities: Precompetitive Collaborative and Data Sharing Initiatives	Examines the nature, impact, and successes of a series of cross industry initiatives covering areas such as structural evaluation (Q)SAR, data sharing–aromatic amines, boronic acids, purging and degradation.	Elder, D. P.; Williams, R.; Harvey et al.(10)
Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk As Impurities in Final Drug Products?	Examines evidence that indicates that in the case of both sulfonyl and acyl chlorides that Ames positive results relate to generation of a reactive species, halodimethyl sulphides (HDMSs) through reaction with DMSO and that this is the root cause of a positive response. Confirmatory negative data from other test solvents is also provided	Amberg, A.; Harvey, J.; Spirkl, H.-P. et al.(11)
Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity	The primary purpose is to raise awareness of the potentially mutagenic nature of boronic acids and stimulate further discussion/research in the areas. It provides mutagenicity data for some 40+ examples, examining the current status of in silico predictions and postulates a potential mechanism related to oxidation of boronic acids to yield oxygen radicals	Hansen, M. H.; Jolly, R. A.; Linder, R. J.(12)
A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors	Details an experimental approach that utilizes kinetic analysis to facilitate assignment of reactivity purge values.	Betori, R. C.; Kallemeyn, J. M.; Welch, D. S.(13)
A Generic Industry Approach to Demonstrate Efficient Purification of Potential Mutagenic Impurities (PMIs) in the Synthesis of Drug Substances	Based on vortioxetine and its associated PMIs predicted purge values based on the system described by Teasdale et al.(15) are compared with experimental values. The results show good correlation concluding that theoretical purge values can be used to predict purging of PMIs.	Lapanja N, Zupanĉiĉ B, Toplak Ĉasar R et al(14)
Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates versus Measured Amounts	The purging of MIs associated with the synthesis of MK-8876 were assessed using the approach described by Teasdale et al.(15)These predicted values were compared to measured values and shown to be conservative in comparison to experimental data.	McLaughlin, M.; Dermenijan, R. K.; Jin, Y. et al.(16)

Several papers focused on control options, specifically ICH option 4, involving evaluation of the impact of process conditions upon the purging of mutagenic impurities. This concept was first described by Teasdale et al. in 2010(17) and augmented by a cross-industry evaluation published in 2013.(15) The practical use of such tools is examined through two papers, that of Nevenka et al.(14) and McLaughlin et al.(16) This is augmented by a further publication by Welch et al.(13)that describes work now being undertaken by an industry consortium to develop this tool still further as a robust in silico tool (Mirabilis). Welch et al. describe the work being undertaken to fully evaluate the potential fate of MIs under a range of common chemical transformations. A critical finding of these studies, examined through the reaction of benzyl bromide with triethylamine, was alignment between the rate constants and half-lives of the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol (Figure 2). This established the proof of concept that the kinetic information obtained from the stand-alone reaction can be used to predict impurity conversion in a more complex reaction.

Figure 2. Alignment between the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol.

Another area addressed in the special edition is that of sulfonate esters. This relates to the use of a sulfonic acid, used to form an API salt and the potential formation of sulfonate esters through reaction with alcoholic solvents. Snodin and Teasdale(9) have reviewed the available literature information concluding that the extensive evidence supports the view that such concerns are grossly exaggerated. In parallel to this publication there have been a series of correspondences involving the EMA quality working party, the following points were released following discussion at the CVMP committee.(18)

“The Committee endorsed the QWP response to the EDQM request for an opinion on new information on alkyl sulfonates. The QWP reviewed the article from Snodin et al. QWP acknowledges the scientific rationale in this article and that the formation of alkyl sulfonates is very low and very much depends on the reaction conditions. This makes the presence of these mutagenic impurities at toxicologically significant levels unlikely. However, as the presence and formation of these alkyl sulfonates cannot be totally excluded, QWP proposes the following approach: marketing authorization holders should justify via Risk Assessment that alkyl sulfonates are not expected to be present for their product, which may be sufficient.”

Of concern within this text is the comment that the presence and formation cannot be totally excluded; this is despite the evidence pointing clearly to fact that it can.

Similarly at the end of February EDQM issued a press release relating to the Mesilates Working party.(19) Included within this, as well as information relating to analytical methods, was the following revision of the production statement.

“In addition to the elaboration of these methods, the Ph. Eur. Commission had also decided to revise the Production section of monographs on those active substances to further assist users: “It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.”

This also goes on to state that:

“Marketing Authorisation Applicants are not obliged to perform the testing when they can justify via risk assessment that alkyl sulfonates are not expected to be present in their product.”

Although both the QWP deliberation and the EDQM statement fall short of concluding minimal risk, they nevertheless represent for the first time at least tacit recognition that control is possible.

read ………….https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Regional_Discussion_Groups/Southern_California_Pharmaceutical/SCPDG%20Impurities_Olsen%20Jan%20event.pdf

Q7 Good Manufacturing Practice
Code Document Title Previously coded
- Q7Good Manufacturing Practice Guide for Active Pharmaceutical IngredientsQ7A
- Q7 Q&AsQuestions and Answers: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html
Finalised Q&As: June 2015

Q7 Questions and Answers

Concept Paper

Work Plan

Finalised Guideline:
November 2000

Q7

Concept Paper

References

1.ICH Q3D Guideline for Elemental Impurities.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf(Dec 16, 2014).
2.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Training_package_Module_0-7.zip
3.Analysis of Oligonucleotides and their related substances; Okafo, G., Elder, D., and Webb, M., Eds.; Chapter 2, pp 22– 28; ChromSoc Separation Sciences Series ISBN 9781906799144.
4.http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/m5192.pdf
5.ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_Step_4.pdf (June 23, 2014).
6.Elder, D. E.; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1437– 1446, DOI: 10.1021/op500346q
7.Kleinman, M. H.; Teasdale, A; Baertschi, S. W. Org. Process Res. Dev. 2015, 19, 1447– 1457, DOI: 10.1021/acs.oprd.5b00091
8.Strege, M. A.; Osborne, L. M.; Hetrick, E. M. Org. Process Res. Dev. 2015, 19, 1458– 1464, DOI: 10.1021/acs.oprd.5b00112
9.Snodin, D; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1465– 1485, DOI: 10.1021/op500397h
10.Elder, D. P.; Williams, R; Harvey Org. Process Res. Dev. 2015, 19, 1486– 1494, DOI: 10.1021/acs.oprd.5b00128
11.Amberg, A.; Harvey, J.; Spirkl, H.-P. Org. Process Res. Dev. 2015, 19, 1495– 1506, DOI: 10.1021/acs.oprd.5b00106
12.Hansen, M. H.; Jolly, R. A.; Linder, R. J. Org. Process Res. Dev. 2015, 19, 1507– 1516, DOI: 10.1021/acs.oprd.5b00150
13.Betori, R. C.; Kallemeyn, J. M.; Welch, D. S. Org. Process Res. Dev. 2015, 19, 1517– 1523, DOI: 10.1021/acs.oprd.5b00257
14.Lapanja, N.; Zupanĉiĉ, B.; Toplak Ĉasar, R. Org. Process Res. Dev. 2015, 19, 1524– 1530, DOI: 10.1021/acs.oprd.5b00061
15.Teasdale, A.; Elder, D.; Chang, S.-J. Org. Process Res. Dev. 2013, 17, 221– 230, DOI: 10.1021/op300268u
16.McLaughlin, M.; Dermenjian, R. K.; Jin, Y. Org. Process Res. Dev. 2015, 19, 1531– 1535, DOI: 10.1021/acs.oprd.5b00263
17.Teasdale, A.; Fenner, S.; Ray, A Org. Process Res. Dev. 2010, 14, 943– 945, DOI: 10.1021/op100071n
18.http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2015/12/WC500198748.pdf (Dec 8, 2015).
19.https://www.edqm.eu/sites/default/files/press_release_on_mutagenic_impurities_february_2016.pdf (Feb 25, 2016).
20.Pharmaceutical CGMPS for the 21st Century—A Risk-Based Approach.http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM176374.pdf (Sept 2004).
21.Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (July 28, 2014).
22.ICH Q9—Quality Risk Management.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf (Nov 9, 2005).
23.ICH Q10—Pharmaceutical Quality System.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf (June 4, 2008).
24.Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM448638.pdf?_sm_au_=iNH61FD2WjHZP02F (May 2015).

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FDA´s new policy regarding grouping of supplements for CMC changes

regulatory Comments Off

May 192016

The US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes. Find out more about Policy and Procedures regarding the Review of Grouped Product Quality Supplements.

http://www.gmp-compliance.org/enews_05320_FDA%B4s-new-policy-regarding-grouping-of-supplements-for-CMC-changes_15173,Z-RAM_n.html

On April 19, 2016 the US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) released a new document outlining how supplements can be grouped together and submitted concurrently for the same chemistry, manufacturing and controls (CMC) changes to multiple approved new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biological license applications (BLAs) submitted by the same applicant.

The agency says the goal of its new policy is to make the process more efficient and consistent when reviewing grouped supplements.The term “grouped supplements” is used to describe two or more supplements reviewed and processed using the procedures set forth in the new document, though FDA makes clear that supplements cannot be grouped if submitted by a different applicant or if the supplements provide for different CMC changes. “The supporting data necessary for the review of the CMC changes should be the same for each of the grouped supplements,” FDA says. “Any supplement that provides for the same CMC changes but necessitates the review of data that is unique to that supplement (e.g., product-specific data) should not be grouped.”

Supplements can be grouped when the following criteria are met:

The cover letter for the supplements clearly states the purpose of the proposed CMC changes and indicates that the supplement is one of multiple submissions for the same change.
Each supplement includes a list of the application numbers (NDA, BLA, and ANDA, as appropriate) and identifies the drug products that will be covered by the CMC changes.
The supplements have the same submission date on Form FDA 356h.

“On a case-by-case basis, the Center may also group supplements that do not meet some or any of the criteria described above, if grouping the supplements is advantageous to the review process,” FDA says.

Circumstances where this may occur include cases when an applicant submits a group of supplements for the same CMC change and then, at a later date, submits additional supplements for the same change and requests FDA officials to include the second set of supplements in the group.

The Regulatory Business Project Manager (RBPM) and Branch Chief (BC) of the relevant review division will decide on a case-by-case basis whether such changes will be allowed, though FDA notes that “consideration will be given to whether the goal date for the original group of supplements could still be met if the second set of supplements is added to the review.”

Additionally, seven new procedures were outlined by FDA in the MAPP (Manual of Policies and Procedures).

Source: Regulatory Affairs Proffessional Society – See more at: OFFICE OF PHARMACEUTICAL QUALITY Review of Grouped Product Quality Supplements

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