National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India

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DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

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////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO



EMA modernizing the Orphan designation process

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EMA modernizing the orphan designation process

On June 19, 2018, the European Medicines Agency (EMA) launched a new secure online portal for Orphan Designation (OD) applications. The portal, named ‘Iris’, provides a single window where applicants can submit and manage the information and documents related to their applications for orphan designation ref 1. This initiative is expected to reduce the time required to prepare and submit the applications. During the review process, applicants can check the status of their applications from any device and receive automatic notifications when the status of the application changes.

About Iris

IRIS is the online web portal through which applicants can apply to the EMA for orphan designation for a medicine. EMA plans to expand the scope of this portal to cover other regulatory and scientific procedures. This new process, which will become mandatory after September 19, 2018, for procuring orphan designation, requires the following steps to be completed before any activity relating to an orphan designation procedure can be carried out using the new IRIS Portal ref 2:

a) Both the Applicant and Sponsor of an orphan designation, or persons acting on their behalf, must have an active EMA user account and must be registered with IRIS user access roles of either ‘Orphan Industry Manager’ or ‘Orphan Industry Contributor.

b) The ‘Organization’ for which the OD application is being submitted must be registered in the EMA’s Organization Management System (OMS);

c) The ‘Substance(s)’ for which the application is being submitted must be registered and appear on the official EMA list of all substances, the European Union Telematics Controlled Terms (EUTCT) database;

d) Each new OD application must have a Research Product Identifier (RPI) – the process for requesting an RPI will be required before OD application.

About orphan drug designation

The European Medicines Agency (EMA) plays a central role in facilitating the development and authorization of medicines for rare diseases, which are termed ‘orphan medicines’ in the medical world. The medicine must fulfil following criteria for designation as an orphan medicine so that it can benefit from incentives such as protection from competition once on the market

It must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;

The prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;

No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

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Modernising the orphan designation process

EMA launches new submission portal today

The European Medicines Agency (EMA) has launched a new secure online portal for orphan designationExternal link icon applications.

The portal, named ‘Iris’, provides a single space where applicants can submit and manage the information and documents related to their applications for orphan designation. This is expected to reduce the time needed to prepare and submit the applications. During the review process, applicants can check the status of their applications from any device and receive automatic notifications when the status of the application changes.

Iris is part of a longer-term programme that aims to make the handling of product-related applications easier and utilises the domains of master data in pharmaceutical regulatory processes (SPOR).

Applicants will still be able to use the existing submission process until 19 September 2018. However, the Agency strongly encourages companies to start using the new portal from today.

In order to help applicants with the transition, EMA has developed two guidance documents. These step-by-step guides provide detailed instructions on how to use the new system and explain what has changed with its introduction.

EMA tested a pilot of the new system in March 2018 with 35 volunteers from 26 different organisations. Feedback from this test helped EMA to optimise the portal and showed high levels of satisfaction.

In future, the new system may be extended to include other procedures, taking user feedback and experience into account.



Note- In order to help applicants with the transition, EMA has developed two guidance documents. These stepby-step guides provide detailed instructions on how to use the new system and explain what has changed with its introduction.

//////iris, ema, orphan designation process

Elemental Impurities

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Elemental Impurities

On January 1, 2018, new guidelines regarding elemental impurities in brand and generic drug products went into effect. Elemental impurities, such as arsenic and lead, pose toxicological risks to patients without providing any therapeutic benefit. These impurities may be present in drug products from a variety of sources, such as interactions with equipment during the drug manufacturing process.

FDA, together with other organizations, such as the International Council for Harmonisation (ICH) and the U.S. Pharmacopeial Convention (USPC), have engaged in long-standing efforts to best protect patients from the risks posed by elemental impurities by developing limits for their amounts in drug products, and standardized approaches to use in determining the amount of elemental impurities in these products.

As of January 1, 2018:

  • All new and existing NDAs and ANDAs for drug products with an official USP monograph are required to meet the requirements in USP General Chapters <232> and <233> for the control of elemental impurities.
  • Applicants submitting NDAs and ANDAs for drug products without a USP monograph are expected to follow the recommendations in the ICH Q3D Elemental Impuritiesdisclaimer icon guideline.

Questions and Answers on Elemental Impurities

Why were these guidelines developed, and why are they important?

Heavy metal elemental impurities pose serious risks to patients without providing a benefit. Modern methods provide better analytical tests to detect elemental impurities, which in turn, will help protect patients by ensuring approved products have safe levels of these impurities. The ICH guidelines and USP General Chapters <232>Elemental Impurities—Limits are focused on establishing Permitted Daily Exposures (PDEs) for elemental impurities in drug products. USP General Chapter <233>Elemental Impurities—Procedures describes analytical approaches for the detection of elemental impurities. The analytical approaches described in <233> are based on modern analytical capabilities, replace the outdated tests in the deleted USP General Chapter <231> Heavy Metals, and allow us to more precisely measure impurities to ensure safe levels. FDA, ICH, USP, and industry experts worked together to develop the new standards that are in alignment and help ensure high quality medicines.

How has FDA been supporting industry to implement the requirements?

FDA, ICH, and USP have all engaged with brand and generic drug manufacturers to support implementation of these requirements. These requirements are the result of long-standing efforts, and both ICH and USP included industry participants on their expert panels that developed these standards. With that input, an implementation date was identified that provided firms with substantial time to verify their operations met the requirements.

In June 2016, FDA published a draft guidance, Elemental Impurities in Drug Products, to provide recommendations regarding the control of elemental impurities of human drug products. The draft guidance encouraged the early adoption of ICH Q3D guidelines and USP General Chapters <232> and <233> before the January 1, 2018 implementation date. FDA has also presented on this topic at conferences, including at a two-day ICH Q3D regional workshop it hosted in August 2016 1. These outreach efforts have supported efforts by industry to perform the risk assessments needed to implement the new guidelines in order to have complete, approvable applications. On an application-specific level, FDA began noting this requirement in complete response letters to applicants that contained quality deficiencies in Spring of 2017.

What should companies do if they have questions about elemental impurity standards?

Companies that have quality questions regarding elemental impurities and their applications should contact the Regulatory Business Process Manager (RBPM) in the Office of Program and Regulatory Operations, Office of Pharmaceutical Quality for their application. Applications that do not meet the elemental impurity guidelines are unable to be approved and applicants may receive a request for the information from the FDA in the form of an Information Request or a Complete Response letter. Firms should submit information on their elemental impurity risk assessments to FDA as soon as they are able, rather than waiting for a request from FDA, in order to minimize the impact on review and approval timeframes. The following resource may help applicants understand the process moving forward depending on where they are in the review process.

What is the International Council for Harmonisation?

ICH, first created in 1990 by regulatory agencies and both brand and generic drug manufacturing associations from the United States, Europe, and Japan, was established to facilitate international collaboration, and has been successful in standardizing and elevating drug development practices throughout the world. ICH’s mission helps to increase patient access to safe, effective, and high quality pharmaceuticals, and to ensure that pharmaceuticals are developed and registered efficiently. International harmonization of regulatory standards means that pharmaceutical manufacturers and developers will be held to the same standards in different markets (countries), which will make the development and delivery of quality pharmaceuticals to the public more timely and efficient. The ICH Website includes training modules on implementation of the Q3D elemental impurity guidelines.

What is the U.S. Pharmacopeia Convention?

The United States Pharmacopeia Convention (USPC) is a private non-profit organization that develops public standards related to pharmaceutical quality. USP General Chapters <232>Elemental Impurities—Limits, and, <233>Elemental Impurities—Procedures are applicable to compendial drug products as per Federal Food, Drug, and Cosmetic Act Sec. 201(j), and Sec. 501(b). USP’s website offers information regarding the history of actions they have taken on elemental impuritiesdisclaimer icon, as well as other FAQdisclaimer icon.

1 Other presentations include the Drug Information Association’s CMC Workshop 2015disclaimer icon, the Consumer Healthcare Products Association’s 2015 Regulatory, Scientific & Quality Conferencedisclaimer icon, the Product Quality Research Institute (PQRI) / USP Workshop on ICH Q3D Elemental Impurities Requirementsdisclaimer icon, the Generic Pharmaceutical Association (now Association of Affordable Medicines) CMC Workshopdisclaimer icon, the USP Excipients Stakeholder Forum, the PQRI/USP Workshop on Implementation Status of ICH Q3Ddisclaimer icon, and the PQRI/USP Workshop on ICH Q3D Elemental Impurities Requirements – Recent Experience and Plans for Full Implementation in 2018disclaimer icon

Elemental Impurities

Efforts in this area are currently focused on three fronts:

  • Finalization of risk assessments to ensure compliance with the ICH Q3D guideline for all products supplied to those markets having implemented ICH Q3D and to the date for implementation

  • Continued development of ICH Q3D dermal limits

  • Removal of the heavy metals limit test USP <231>

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Marketed Product Compliance

When it was published at the end of 2014, ICH Q3D(1) provided a 3 year moratorium in relation to established products, meaning that all such products would have to demonstrate compliance with the guideline at the end of 2017. Many involved will testify to the Herculean effort required to complete this within large organizations where hundreds if not thousands of products were within scope. What has been the outcome? Informal feedback within the industry is that aside from a small number of products, organizations have found that the vast majority of products assessed require no additional control measures because they already have appropriate quality control measures.

Elemental Impurities within Excipients

The ICH Q3D guideline describes how a risk-based approach to the control of elemental impurities in drug products can be taken, highlighting within this that assessments should be data-driven. Options in terms of data include both data generated specific to a drug product and published data. In 2015 the U.S. Food and Drug Administration (FDA) and the European International Pharmaceutical Excipient Council (IPEC) jointly published the outcome of a focused study on some 200 excipient samples covering a range of excipients. This concluded that the overall risk associated with excipients, including those that are mined, was relatively low, especially when typical proportions in formulated drug products were considered. With the express aim of building upon this initial study, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of over 25 000 elemental determinations for over 200 different excipients and represents the largest known, and still rapidly expanding, collection of data of this type.
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A recently published analysis of the database(2) examined a series of aspects, including data coverage as well as impurity levels and variability (across supplier/grade, etc.). The database includes results from multiple analytical studies for many of the excipients and thus can give a clear indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The results are telling. Critically, the data confirm the findings of earlier, smaller FDA–IPEC studies showing that elemental impurity concentrations in excipients, including mined excipients, are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk.
The database is now in active use within member organizations, providing real evidence in support of holistic ICH Q3D risk assessments and in the future potentially significantly reducing the need for testing. However, it is necessary to recognize that there was a sense that mined excipients could still present a risk over the long term. That variability in elemental impurity levels within mined excipients will vary over time, and further data will be required. There is therefore a need for continued collaboration between the pharmaceutical industry and excipient manufacturers.
It is interesting to reflect that had such studies been conducted ahead of finalization of ICH Q3D, it is possible that it would have allowed us to eliminate concerns about elemental impurities, at least for some low-risk excipients Another study could have achieved the same outcome for manufacturing equipment.
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Removal of Heavy Metals Testing

Perhaps our biggest challenge as an industry in this area relates to the potential to remove existing empirical testing for elemental impurities using the wet-chemistry heavy metals limit test because of differences in the global regulatory landscape. In the case of the United States Pharmacopeia (USP), this takes the form of the now-deleted USP Chapter <231>.
On the basis of the time scale for implementation of ICH Q3D, most organizations are well-advanced in terms of the risk assessment of current products, as described above. In the clear majority of cases, this successfully demonstrates that the heavy metals test does not provide any additional control for elemental impurities. On this basis, it should therefore be possible to remove the heavy metals limit test, of which USP <231> is the most prevalent example.
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The situation in the U.S. is that removal is relatively straightforward, as the test has already been removed from the USP. A statement to confirm completion of an elemental impurity risk assessment is then provided in the product annual update. Elsewhere, the situation is more challenging. In Europe there is no definitive position, but filing a simple show-and-tell type 1A variation seems to provide a pathway. Thereafter, the situation is considerably more complex.
In Japan, the equivalent of the USP <231> test has been retained in the Japanese Pharmacopeia (JP). Consequently, removing the test from an existing product (one where a monograph is published and it includes such a test) may require submitting a product-specific request to revise the individual monograph. It is also anticipated that removal of the test from approved but not monographed products will also require a post-approval change submission.
In China, the Chinese Pharmacopeia (CP) will retain the test until at least 2020, and the indication is that the test should still be performed where registered.
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Outside of ICH regions, the situation is still more complicated. Given the prevalent position of the USP in many countries, API and product specifications often include USP <231>. However, this test no longer exists! The challenge then concerns whether the test can be removed and the specification revised, and if so, how this should be done. The scale of this is significant, especially if a formal variations procedure is needed. One apparent option is to continue testing, but even this is complicated, as it is not clear how one could continue to use a test that no longer exists in the USP. Some organizations have even considered developing a “USP <231>-like” test.
Clearly, organizations do not want to continue to use an empirical test when a risk assessment has shown that it adds no value, but at present there is no obvious way to resolve this conundrum for globally marketed products until significant harmonization in compendial test requirements is achieved.
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1 Guideline for Elemental Impurities Q3D, Current Step 4 version, dated Dec 16, 2014.
Boetzel, R.Ceszlak, A.Day, C.An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk AssessmentJ. Pharm. Sci. 2018DOI: 10.1016/j.xphs.2018.04.009
//////////Elemental Impurities, ICH Q3D, USP

ICH Q12: Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

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ICH Q12: Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, 1-2

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Recent ICH quality guidelines (Q8–Q11)(3−6) have focused on providing guidance on the development and manufacture of drug substances (Q11)(6) and drug products (Q8),(3) showing “baseline” and “enhanced” scientific approaches, and utilizing quality risk management tools (Q9) within the pharmaceutical quality management system (Q10). To further support the implementation of these development and manufacturing approaches, ICH recognized the value in providing tools and approaches for the management of post-approval chemistry, manufacturing, and controls (CMC) changes based on product and process understanding that could be employed by all ICH participants. Several useful tools had been established in different regions, and it was recognized that pharmaceutical innovation and continuous improvement would be optimally supported if best practices could be employed in similar ways across the regions. Achieving this harmonization would result in more efficient manufacture and change and would also increase the value of the pharmaceutical quality system and support continued optimization of the utilization of valuable resources within regulatory agencies and inspectorates (e.g., toward oversight of critical rather than noncritical changes, incentivizing industry’s understanding and management of manufacturing). The ICH Concept Paper for the development of this guidance was endorsed in 2014.(7)
The drafted consensus document is now available for public comment (step 2 of the ICH process),(8) with comments being collected by the regions during 2018 (with various comment deadlines).
The draft guidance includes some potentially very important approaches for future CMC change management, and importantly, the tools and approaches being developed are seen as usable across the range of pharmaceutical product types (including drug–device combinations) and applicable to existing products as well as newly approved products.
An approach of particular importance that is included in the guideline is the “post-approval change management protocol” (PACMP), which allows for specific changes to be predescribed to regulators and agreement to be reached on the scientific approach and data expectations that will support the change. This ability to predefine how to successfully make a change will bring great clarity and predictability to the planning and prosecution of, particularly, complex change types (often viewed as major changes needing “prior approval” in current regulatory change systems). Furthermore, the predetermination of data necessary to support the change allows for the final communication of the change to be a simple matter of confirming the suitability of the change with the expected data and for the regulatory change class to be reduced on the basis of the prior agreement of the change management approach. Importantly, a PACMP can be either agreed for a single change for a single product or constructed and agreed in a more wide-ranging manner to support multiple similar changes to be conducted on more than one product. This is of immense potential value to industry and regulators alike. Annex II of the draft guideline provides illustrative examples of different types of PACMPs, giving an example of a PACMP for a single change (to a manufacturing site for a drug substance) and an example of the more general management of such a site change.
In a section of the guideline on supporting post-approval changes for marketed products, where considerable manufacturing experience has been accrued, important approaches are given for the management of changes in analytical procedures and discussing how data requirements for changes (for stability data) can be impacted by product and process understanding.
In addition, the guidance seeks to provide an approach to differentiate the levels of regulatory oversight of particular changes on the basis of known impact and criticality of the potential change to product quality. The ability to differentiate change expectations on the basis of actual product understanding is a natural extension of the approaches taken in ICH Q8 and Q11, where for example product and process understanding can establish a “Design Space” for manufacturing and control within which changes are not seen as requiring regulatory oversight. In the draft of Q12, this concept is further developed by the concept of “Established Conditions” (ECs), with discussion of how investment in understanding can impact submission expectations (with Appendix I of the draft guideline providing an illustration of CTD sections that contain ECs and Annex I suggesting illustrative examples of ECs for both chemical products and biological products) and post-approval change management expectations. Importantly, the guidance discusses how this approach could be used for existing products, where the manufacturing process may have been described without any differentiation of change management expectations, leading to inefficient use of both industry and regulatory resources.
The draft guideline also includes a suggested system for the collation of such “agreed” regulatory change mechanisms for a product via use of a product lifecycle management (PLCM) approach, wherein the agreed changes can be clearly collated alongside the manufacturing commitments and the agreed (lesser) change reporting category for the changes. Annex III of the draft documentation provides an example of a PLCM document.
The guideline also contains content describing the pharmaceutical quality system (PQS) change management expectations (with Appendix II of the guideline providing further illustration of principles of change management) and the relationship between industry and regulators and importantly between regulatory assessment and inspection needed to support strong implementation of the approaches within Q12.
The draft guideline clearly already provides tools and approaches for change management of immense potential value. Nevertheless, the opportunity to comment on the draft is always an important step in the development of an ICH guideline, and it is important to ensure that comments assist in providing the clearest possible final guidance that will be readily and consistently implemented to mutual industry and regulator benefit. It is noteworthy that the current draft of the guideline includes wording suggesting that some concepts may not be implementable at the current time across every region. It will be of greatest benefit if the tools and approaches as described and agreed in the finalized guidance will be available for use on as wide a global basis as possible, in line with the ongoing vision of ICH for science-based, harmonized, and efficient regulation of pharmaceuticals.
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3  Pharmaceutical Development Q8(R2), Current Step 4 version, dated August 2009.
4 Quality Risk Management Q9, Current Step 4 version, dated Nov 9, 2005.
5 Pharmaceutical Quality System Q10, Current Step 4 version, dated June 4, 2008.
6 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Q11, Current Step 4 version, dated May 1 2012.
7 Final Concept Paper Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, dated July 28 2014, endorsed by the ICH Steering Committee on Sept 9, 2014.
8 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Q12, draft version endorsed on Nov 16, 2017.

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