AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

From lab to patient: journey of a medicine. EMA

 EMA, EU, regulatory, Uncategorized  Comments Off on From lab to patient: journey of a medicine. EMA
Sep 092021
 

From lab to patient: journey of a medicine. EMA

Interactive timeline - Lab to patients thumbnail

Follow the journey of a medicine for human use assessed by EMA in this interactive timeline. It explains all stages from initial research to patient access, including how EMA supports medicine development, assesses the benefits and risks and monitors the safety of medicine

  • From laboratory to patient: the journey of a centrally authorised medicine (PDF/1.75 MB)

    First published: 04/03/2019
    Last updated: 10/02/2020

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API, Impurities and Regulatory aspects

 regulatory, Uncategorized  Comments Off on API, Impurities and Regulatory aspects
Oct 242018
 
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The impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product
Impurities is defined as an entity of drug substances or drug product that is not chemical entity defined as drug substances an excipients or other additives to drugproduct.

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. Structure elucidation of pharmaceutical impurities is an important part of the drug product development process. Impurities can have unwanted pharmacological or toxicological effects that seriously impact product quality and patient safety. Potential sources and mechanisms of impurity formation are discussed for both drugs. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities. In this review, a description of different types and origins of impurities in relation to ICH guidelines and, degradation routes, including specific examples, are presented. The article further discusses measures regarding the control of impurities in pharmaceuticals substance and drug product applications.

Impurities in pharmaceuticals are the unwanted chemicals that remain with the active pharmaceutical ingredients (APIs), or develop during formulation, or upon aging of both API and formulated APIs to medicines. The presence of these unwanted chemicals even in small amounts may influence the efficacy and safety of the pharmaceutical products.

According to ICH, an impurity in a drug substance is defined as-“any component of the new drug substance that is not the chemical entity defined as the new drug substance”. There is an ever increasing interest in impurities present in APIs recently, not only purity profile but also impurity profile has become essential as per various regulatory requirements. The presence of the unwanted chemicals, even in small amount, may influence the efficacy and safety of the pharmaceutical products.

“In the pharmaceutical world, an impurity is considered as any other organic material, besides the drug substance, or ingredients, arise out of synthesis or unwanted chemicals that remains with API’s”

The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities.

CLASSIFICATIONS OF IMPURITIES:
Impurities have been named differently or classified as per the ICH guidelines as follows:

A] Common names
1. By-products
2. Degradation products
3. Interaction products
4. Intermediates
5. Penultimate intermediates
6. Related products
7. Transformation products

B] United State Pharmacopeia
The United States Pharmacopoeia (USP) classifies impurities in various sections:
1. Impurities in Official Articles
2. Ordinary Impurities
3. Organic Volatile Impurities

C] ICH Terminology
According to ICH guidelines, impurities in the drug substance produced by chemical synthesis can broadly be classified into following three categories –
1. Organic Impurities (Process and Drug related)
2. Inorganic Impurities
3. Residual Solvents

Organic impurities may arise during the manufacturing process and or storage of the drug substance may be identified or unidentified, volatile or non-volatile, and may include
1. Starting materials or intermediates
2. By-products
3. Degradation products

Impurities are found in API’s unless, a proper care is taken in every step involved throughout the multi-step synthesis for example; in paracetamol bulk, there is a limit test for p-aminophenol, which could be a starting material for one manufacturer or be an intermediate for the others. Impurities can also be formed by degradation of the end product during manufacturing of the bulk drugs.

The degradation of penicillin and cephalosporin are well-known examples of degradation products. The presence of a β-lactam ring as well as that of an a-amino in the C6 or C7 side chain plays a critical role in their degradation.

The primary objectives of process chemical research are the development of efficient, scalable, and safe reproducible synthetic routes to drug candidates within the developmental space and acting as a framework for commercial production in order to meet the requirement of various regulatory agencies. Therefore, assessment and control of the impurities in a drug substance and drug product are important aspects of drug development for the development team to obtain various marketing approvals. It is extremely challenging for an organic chemist to identify the impurities which are formed in very small quantities in a drug substance and wearisome if the product is nonpharmacopeial. A study describes the formation, identification, synthesis, and characterization of impurities found in the preparation of API. A study will help a synthetic organic chemist to understand the potential impurities in API synthesis and thereby obtain the pure compound.
Care to taken ensure that desired drug metabolism, safety and clinical studies are not jeopardized by inconsistent purity or impurities having potential harmful toxicological properties,
As regulatory guidelines promulgated by the International Conference on Harmonization (ICH)(1) dictate rigorous identification of impurities at levels of 0.1%,
It is important to develop commercially viable processes for drug substance manufacture to allow greater and more affordable access in the health care sector. In regard to the process development of drug substances, it is essential to know the origin and method of control of any unwanted substances present in it. The limit should be controlled under the threshold of toxicological concern (TTC) for the purpose of ensuring safety and efficacy of the drug and to meet the requirements of various drug regulatory agencies.(2,3)
The impurities in drug substances mostly come from starting substrates, reagents, solvents, and side reactions of the synthetic route employed. Therefore, assessment and control of the undesired substances is an essential aspect of the drug development journey, with special consideration of patient health risk.(4,5)
The isolation/synthesis and characterization of process-related critical impurities (more difficult to control under the desired regulatory limits) of any drug substance in order to evaluate their origin/fate and thereafter their control strategies in the developed process as per International Council for Harmonisation (ICH) guidelines.(4)
The goal of pharmaceutical development is to develop process understanding and control which will yield procedures that consistently deliver products possessing the desired key quality attributes. To achieve this, the quality by design (QbD) paradigm has been employed in combination with process-risk assessment strategies to systematically gather knowledge through the application of sound scientific approaches.(6)
Ganzer et al. recently published an article about critical process parameters and API synthesis.(7) The article presented an in-depth discussion of a stepwise, process risk assessment approach to facilitate the identification and understanding of critical quality attributes, process parameters, and in-process controls. The primary benefit of working within the QbD conceptual framework and employing process risk assessment strategies is the reproducible delivery of high-quality active pharmaceutical ingredient (API). However, a secondary benefit is the ability to obtain regulatory flexibility with respect to filing requirements.(8)
The control of impurities observed in an API is critical in delivering an API of high quality. Identification and understanding of the mechanism of formation of process-related impurities are critical pieces of information required for the development of control strategies. In addition, to ensure a continuing supply of API for drug product clinical manufacture, timely identification of key impurities is essential. These synthesis-related impurities and their precursors are considered as critical impurities because they directly affect the quality and impurity profile of the API. It is our practice that critical impurities be identified if practicable. Therefore, the timely identification of critical impurities becomes an integral part of process development.
There are different approaches to the identification of impurities. Described, herein, a general strategy that we have used in our laboratory, which leads to the rapid identification of impurities. To identify the structure of a low-level unknown impurity, we usually use liquid chromatography/mass spectrometry (LC/MS)/high-resolution MS (HRMS) and tandem MS (MS/MS) for molecular weight (MW) determination, elemental composition, and fragmentation patterns. On the basis of the mass spectrometric data and knowledge of the process chemistry, one or more possible structure(s) may be assigned for the impurity, with definitive structure information obtained by inspection of the HPLC retention time, UV spectrum, and MS profile of an authentic compound.
If an authentic sample is not available, the isolation of a pure sample of the impurity is undertaken for structure elucidation using NMR spectroscopy. The isolation of low-level impurities is usually conducted using preparative HPLC chromatography
REFERENCES
 1 ICH Q3A Impurities in New Drug Substances, R2International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)Geneva, Switzerland, October 2006http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf.
  • 2. Patil, G. D.; Kshirsagar, S. W.Shinde, S. B.Patil, P. S.Deshpande, M. S.Chaudhari, A. T.Sonawane, S. P.Maikap, G. C.Gurjar, M. K.Identification, Synthesis, and Strategy For Minimization of Potential Impurities Observed In Raltegravir Potassium Drug SubstanceOrg. Process Res. Dev. 2012161422– 1429DOI: 10.1021/op300077m
  • 3. Huang, Y.; Ye, Q.Guo, Z.Palaniswamy, V. A.Grosso, J. A. Identification of Critical Process Impurities and Their Impact on Process Research and DevelopmentOrg. Process Res. Dev.200812632– 636DOI: 10.1021/op800067v

4. ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New Drug SubstancesInternational Conference on HarmonizationGeneva2002.

5. Mishra, B.Thakur, A.Mahata, P. P. Pharmaceutical Impurities: A ReviewInt. J. Pharm. Chem.20155 (7), 232– 239

6 International Conference on Harmonisation (ICH) Guidelines; Q8, Pharmaceutical Development, 2005; Q9, Quality Risk Management, 2006.

GanzerW. R.MaternaJ. A.MitchellM. B.WallL. K. Pharm. Technol. 2005July 21–12.

NasrM. Drug Information Association Annual Meeting, Philadelphia, PA, June 19, 2006; Pharmaceutical Quality Assessment System (PQAS) in the 21st Century, 2006.

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EMA modernizing the orphan designation process

 regulatory  Comments Off on EMA modernizing the orphan designation process
Jul 162018
 

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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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19/06/2018

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.

12 http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/06/news_detail_002976.jsp&mid=WC0b01ac058004d5c1

13 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2018/06/WC500250762.pdf

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

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Elemental Impurities

 regulatory, Uncategorized  Comments Off on Elemental Impurities
Jul 112018
 

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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>

  • Image result for elemental impurities
  • Image result for elemental impurities

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.
Image result for elemental impurities
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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REFERENCES
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
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KemInnTek Laboratories, helps you synthesize in mg to multi-kg scale.

 regulatory, SYNTHESIS, Uncategorized  Comments Off on KemInnTek Laboratories, helps you synthesize in mg to multi-kg scale.
May 122017
 

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KemInnTek Laboratories

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Welcome to Keminntek Laboratories

Keminntek Laboratories is a Hyderabad (India) based Contract Research Organization in Pharmaceutical sector in specific Pharmaceutical Intermediates, Speciality Chemicals, Impurities and Active Pharmaceutical Ingredients. Promoters of Keminntek Laboratories are Young and Dynamic Technocrats and established with a vision to provide a best-in class pharmaceutical services. Keminntek Laboratories would be a value-added and innovative-in –approach business partner. It has a strong talent pool of qualified and experienced scientists drawn from the national and international institutes and industry. It has a capability to synthesize in mg to multi-kg scale.

About Us

Vision
Our vision is to build Keminntek Laboratories into a world class leading pharmaceutical service provider based on innovation while keeping health and prosperity in mind. Imperatively, we will continue our business with high standards of ethics in the interest of society and environment.Mission
We are committed towards improving people’s health through science and innovation. Our mission is to provide better access of the affordable medicines to the patients and positively impact prosperity.

Team

  • Promoters of this company are very well qualified and experienced personalities in Pharmaceutical sector

  • We have a team consisting

    • Ph.Ds from premier Indian Institutes and postdocs from abroad

    • M. Sc (Chemistry) with 2-12 years pharmaceutical industry experience

  • Our team expertise lies in process R&D of pharmaceutical intermediates, NCEs (Medicinal Chemistry) development, pharmaceutical impurities, and custom synthesis of specialty chemicals

http://keminnteklabs.com/

keminnteklabs@gmail.com

 

Kolupula Srinivas

Kolupula Srinivas

Co-Founder & Chief Scientific Officer at Keminntek Laboratories

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Plot No: 10/11, Road No: 5,
IDA Nacharam, Hyderabad,
India – 500076.
 +91 9515 053 169 / 68
 keminnteklabs@gmail.com
 keminnteklabs@gmail.com

 

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//////////////KemInnTek Laboratories, srinivas kolupula, hyderabad, blog, cro, custom, synthesis

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Thailand Drug regulatory Update, Take a peep

 regulatory  Comments Off on Thailand Drug regulatory Update, Take a peep
Jan 192017
 

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http://www.fda.moph.go.th/eng/index.stm

 

[PDF]Regulatory Requirement for the Approval of generic Drug in Thailand …

www.jpsbr.org/index_htm_files/JPSBR14RV4029.pdf

Apr 13, 2014 – Thailand has its own drug registration format and also follows. ASEAN CTD. … Transparency in the regulatory authorities of member countries.

THAILAND PHARMACEUTICAL REGISTRATION AND APPROVAL

The Thai FDA (TFDA), one of several agencies under the Ministry of Public Health (MPH), is the regulatory body administering drugs in Thailand. The Drug Control Division of the TFDA is responsible for registration, licensing, surveillance, inspection and adverse event monitoring for all pharmaceuticals and pharmaceutical companies in Thailand. Foreign pharma companies dominate the Thai drug market. Due in part to trade negotiations, regional harmonization and positive economic trends, the pharmaceutical market in Thailand is predicted to double by 2022.There are several versions of the Drug Act currently in effect, and the Thai government is working on a revised version with updated regulations. Under the current laws, pharmaceuticals are categorized as either traditional or modern medicines, with different applications and oversight. Modern medicines are subdivided into three categories, each of which has separate registration requirements. Licenses currently do not require renewal.

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STR1

 

link……….http://drug.fda.moph.go.th/eng/

FIRST ASEAN COUNTRY WITH A NATIONAL eCTD PROGRAM

News_2

Thai FDA intends to accept dossier in eCTD format: The Drug Regulatory Authority of Thailand (Thai FDA) has initiated the acceptance of Pilot eCTD from October 2014.Read More

eCTD requirements

http://drug.fda.moph.go.th/eng/files/2_eSubmission%20FAQ1_0921.pdf

http://drug.fda.moph.go.th/eng/files/1_TH%20Module%201%20and%20Regional%20Specification_0921_Tch.pdf

http://drug.fda.moph.go.th/eng/files/TH%20Regional%20Specification%20and%20Validation%20Criteria.pdf

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STR1

 

Step to be followed to submit eCTD application

Taken from

https://www.linkedin.com/pulse/deep-dive-thai-ectd-overview-requirement-amar-tandon?trk=hp-feed-article-title-like

Regulatory Scientist at Kinapse

A) Prepare Application to get a eSubmission Identifier for every application issued. A request to the THAI FDA online service should be submitted to obtain an eSubmission identifier which will require following details.

  • Licensee Number
  • Description of Application
  • Dosage Form
  • INN or Generic Name
  • Strength
  • WHO ATC Code
  • Sequence Type
  • Application form
  • CPP (In case of Importer)

The eSubmission Identifier will be issued within 10 days of application. The Applicant must then make an appointment for submission within 30 days.

B) Prepare valid application along with validation reports as per country (Thailand) specific requirement with regional eSubmission Identifier provided.

The M1 requirements to be kept in consideration while compiling the Submission.

  • Enhanced granularity for each sections
  • Country code is not required in filenames
  • Information relating to orphan market is not mandatory
  • For LCM (Life cycle management) submissions the Operation attribute should be “Replace” in Tracking Table
  • Validation report should be submitted along with the sequence
  • 1.3.1 Product Information has been broken down into three specific sections for Labelling, SPC and the Package leaflet. No other product types are expected. If one file is submitted for this section, it should be submitted under 1.3.1.1 Labelling.
  • 1.3.1.3 Package Leaflet has been broken down into language sections for English, Thai and Other languages.
  • It is recommended that separate files should be submitted for each language.
  • Applicants can re-use the content submitted in other regions (including STF).
  • The identifier is a combination of a letter and seven digits.
  • Working documents are not needed and do not need to be provided within the eCTD framework for Thailand
  • Section 1.5.2 “Information for Generic, ‘Hybrid’ or Bio-similar Applications” has been broken down into three sections and given a section number to make expectations and cross referencing clearer.
  • Only one file should be provided for 1.6 Environmental Risk Assessment. It is not allowed to provide content in both 1.6.1 and 1.6.2.
  • During lifecycle, 1.8.2 Risk management plan should always use the lifecycle operator replace.

C) Dispatch Activity Delivery of the application at Thai FDA in CD/DVD (make an prior appointment with HA at drug_esubmissions@fda.moph.go.th

Thai FDA has proposed a set of media formats to be used while submission of eCTD

  • (CD-R) i.e. Compact Disc-Recordable
  • Digital Versatile Disc-Random Access Memory (DVD-RAM)
  • Digital Versatile Disc-Recordable (DVD+R/-R) recorded

Future Aspect-Import: The eCTD will be validated and imported into the THAI FDA Review System

Feedback: Application feedback (if there are problems experienced during the upload) and review of application by Thai FDA

Ensure that you do not use. 1. Double-sided discs 2. Re-writable disc (protection, authenticity and Stability of information cannot

Ensure that you do not use:

  • Double-sided discs,
  • Re-writable discs (protection, authenticity, and stability of information cannot be guaranteed)
  • Compressed or zipped files (except for validation reports)

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

 

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EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?

 regulatory  Comments Off on EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?
Jan 172017
 

 

 

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In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

Image result for Cleaning Validation

http://www.gmp-compliance.org/enews_05736_EMA-publishes-Q-A-on-Health-Based-Exposure-Limits—Does-the-1-1000-dose-criterion-come-again-into-play-in-Cleaning-Validation_15560,15661,15963,Z-VM_n.html

In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

 

some pics

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FDA publishes Final Guideline on GMP for Combination Products

 gmp, regulatory  Comments Off on FDA publishes Final Guideline on GMP for Combination Products
Jan 132017
 

 

Image result for CGMP for Combination Products.

 

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?

http://www.gmp-compliance.org/enews_05738_FDA-publishes-Final-Guideline-on-GMP-for-Combination-Products_15649,16021,15963,Z-VM_n.html

In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:

The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).

In the table of content there are one new subchapter (II B  Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:

I. Introduction

II. Background
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components

III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product

IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)?
A. Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps

V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)

VI. Contact Us

VII. Glossary

VIII. References

In the introduction it is explicitly stated, that “The final rule did not establish any new requirements”. In a footnote the guideline gives an explanation why the term “legacy” combination product has not been used.

In the new subchapter II B  (Quality and Current Good Manufacturing Practice) the guideline mentions, that “the core requirements embedded in these regulations provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. This includes establishing a strong quality management system, using appropriate quality raw materials, establishing robust manufacturing and control procedures based on sound design principles, and detecting and investigating product quality deviations. In addition, these regulations call for ongoing assessment of systems and the implementation of corrective actions where appropriate”.

The final document introduces in Section C the new term “CGMP operating system”. This means the operating system within an establishment that is designed and implemented to address and meet the current good manufacturing practice requirements applicable to the manufacture of a combination product. A clarification about constituent parts of cross-labeled combination products is also implemented. Further, there is a new passage about the choice of the GMP-approach (QS regulation vs drug CGMPs) also regarding a streamlined approach and for companies manufacturing different products. Completely new is the passage with the title “Documentation of CGMP Approach”. Here you can also find hints that manufacturerers with products that have been on the market since before GMP for Combination Products (21 CFR 4) came into operation, have to be compliant too. The guideline requires that the information about the “CGMP operating system” should be shared with FDA investigators in the beginning of an inspection.

In the “Demonstrating compliance” subchapter (III A) there is additional information about crossreferenced approaches (21 CFR 820 vs 21 CFR 211 and vice versa). For investigational products (III B) you can find more detailed information about exemptions from part 820 regarding 21 CFR 820.30 (Design).

In the Definition and terminology section (III D) there are amendments regarding container closure aspects and kits. Section III D (What CGMP requirements apply to a product or facility?) details the responsibility of the owner of a combination product and CAPA procedures in shared facilities.

In section III E. (Control of changes to a combination product) information for single entity and co-packed combination product manufacturers has been amended. The passages in IV A (Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) with regard to 21 CFR 820 about Management Responsibility, Design Controls, Purchasing Controls and CAPA have been extended – including examples – and “modernised”. Terms like quality oversight and QTTP are now mentioned there. Vice versa the passages with regard to 21 CFR 211, 211.84. 211.103, 211.132, 211.137, 211.165, 211.166, 211.167, and 211.170,  (IV B  Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)) have also been extended – likewise with examples – and have been “modernised” as well (e.g. parametric release is mentioned).

In the example about prefilled syringes (V A) one can find an amended passsage about Design Controls and a new section about Design History File. In the example about drug-coated mesh (V B) there has also been included a new section about Design History File. In the drug eluting stent example (V. C) there are amendments in the section about 21 CFR 211.184, 21 CFR 211.103 and 21 CFR 211.170. Furthermore all examples comprise editorial changes.

Completely new is the chapter VII (Glossary). The number of references (Chapter VIII) increased to 31 (draft: 19).

Summary:
There are a lot of changes from the draft to the final document. One chapter (Glossary) and a subchapter ( Quality and Current Good Manufacturing Practices) are new, but there are also new passages and amendments in the final document. Helpful are the examples that have been integrated.

Please also see the Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products for more details.

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EMA issues new Guideline on “Chemistry of Active Substances”

 EMA, regulatory  Comments Off on EMA issues new Guideline on “Chemistry of Active Substances”
Dec 222016
 

Image result for active substances

The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document  entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

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Selection and justification of starting materials: new Questions and Answers to ICH Q11 published

 regulatory  Comments Off on Selection and justification of starting materials: new Questions and Answers to ICH Q11 published
Dec 082016
 

 

The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.

http://www.gmp-compliance.org/enews_05688_Selection-and-justification-of-starting-materials-new-Questions-and-Answers-to-ICH-Q11-published_15619,15868,S-WKS_n.html

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

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

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

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

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

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

Answer:
Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.
The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.

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

Answer:
Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process … . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.
ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.

With the recent publication of this draft Q&A Document with the complete title “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers (regarding the selection and justification of starting materials)” on the ICH website it reached Step 2b of the ICH Process and now enters the consultation period.  Comments may be provided by e-mailing to the ICH Secretariat at admin@ich.org.

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extra info…………
A PRESENTATION

 

 

 

Ever since the FDA issued its landmark guidance Pharmaceutical GMPs-A Risk Based Approach in 2004, the industry has been struggling with how to demonstrate process understanding as a basis for quality. Bolstered by guidance from ICH, specifically Q6-Q10, the pieces have long been in place to build a solution that is philosophically consistent with these best practice principles. Even so, the evolution to process understanding as a basis for quality has been slow. Pressure to accelerate this transformation spiked in 2011 when the FDA issued its new guidance on process validation that basically mandated the core components of ICH Q6-10 as part of Stages 1 and 2. To be fair, enforcement has been uneven and that fact has further impeded adoption, with the compliance inspectors themselves struggling to acquire the necessary skills to fully evaluate statistical arguments of process control and predictability.

One area debated since 2008 is the application of GMPs and demonstration of control for drug substances. Drug substance suppliers and drug product manufacturers have used the tenets of ICH Q7A as the foundation for deciding where GMPs can be reasonably implemented, to establish the final intermediate (FI) and the regulatory starting material (RSM). However, the ability to support the quality of the drug substance has a profound impact on the ability to defend the drug product quality. In the last few years it has become apparent that it was not reasonable to apply the same requirements for drug products to drug substances because the processes can be markedly different. In response to this need, the ICH issued a new guidance; Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). The key ICH documents that impact Q11 are shown in Figure 1.


Figure 1. Guidances Impacting ICH Q11.

The FDA formally adopted ICHQ11 in November 2012 and its purpose is two-fold. First, it offers guidance on the information to provide in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q). Second, and perhaps most importantly, it attempts to clarify the concepts defined in the ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substances.

What makes ICH Q11 so important is its emphasis on control strategy. This concept was introduced in ICH Q10 as “a planned set of controls, derived from current product and process understanding that assures process performance and product quality.”

Within the drug product world, the control strategy concept has been elusive as industry grapples with moving from a sample-and-test concept of quality to one of process understanding and behavior. This concept is even more removed for drug substance manufacturers and, in some cases, is more difficult to implement. But Q11 is much more than a mere framework for control strategy. The guidance is structured very similarly to the concepts discussed in the new 2011 Process Validation guidance. Looking closely, Q11 addresses:
• Product Design/Risk Assessment/CQA Determination
• Defining the Design Space and establishing a control strategy
• Process validation and analysis
• Information required for Sections 3.2.S.2.2 – 3.2.S.2.6 of the eCTD
• Lifecycle management

Product design/Risk assessment/CQA determination

Within the context of process development, the guidance defines similar considerations to those defined in the Stage 1 activity of Process Validation. Understanding the quality linkage between the drug substance’s physical, chemical, and microbiological characteristics, and the final drug products’ Quality Target Product Profile (QTPP), is the primary objective of the product and process design phase. The product’s QTPP is comprised of the final product Critical to Quality Attributes (CQAs). Identifying the raw material characteristics of the drug substance that can impact the drug product is a critical first step in developing a defensible control strategy. Employing risk analysis tools at the outset can help focus the process development activities upon the unit operations that have the potential to impact the final product’s CQAs. In the case of biological drug substances, any knowledge regarding mechanism of action and biological characterization, such as studies that evaluate structure-function relationships, can contribute to the assessment of risk for some product attributes.

Drug substance CQAs typically include those properties or characteristics that affect identity, purity, biological activity, and stability of the final drug product. In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process. When considering CQAs for the drug substance, it is important to not overlook the impact of impurities because of their potential impact on drug product safety. For chemical entities, these include organic impurities (including potentially mutagenic impurities), inorganic impurities such as metal residues, and residual solvents.

For biotechnological/biological products, impurities may be process-related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived impurities (e.g., Host Cell Proteins [HCP] and DNA); cell culture-derived impurities (e.g., media components); and downstream-derived impurities (e.g., column leachable). Determining CQAs for biotechnology/biological products should also include consideration of contaminants, as defined in Q6B, including all adventitiously introduced materials not intended to be part of the manufacturing process (e.g., viral, bacterial, or mycoplasma contamination).

Defining the design space and establishing a control strategy

ICH Q8 describes a tiered approach to establishing final processing conditions that consists of moving from the knowledge space to the process design space and finally the control space. ICH Q8 and Q11 define the Design Space as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.” In the drug product world the terminology typically applied to the design space is the Proven Acceptable Range (PAR) that used to equate to the validated range.

Here is why this is important: the ability to accurately assess the significance and effect of the variability of material attributes and process parameters on drug substance CQAs, and hence the limits of a design space, depends on the extent of process and product understanding. The challenge with drug substance processes is where to apply the characterization. ICH Q7A recognizes that upstream of the RSM does not require GMP control. The design space can be developed based on a combination of prior knowledge, first principles, and/or empirical understanding of the process. A design space might be determined per unit operation (e.g., reaction, crystallization, distillation, purification), or a combination of selected unit operations should generally be selected based on their impact on CQAs.

In developing a control strategy, both upstream and downstream factors should be considered. Starting material characteristics, in-process testing, and critical process parameters variation control are the key elements in a defensible control strategy. For in-process and release testing criteria the resolution of the measurement tool should be considered before making any conclusions.

Process validation

ICH Q11’s description of process validation mimics the same description in ICH Q7A but offers up an alternative for continuous verification that mirrors the concepts in ICH Q8 and the new process validation guidance. As mentioned, the enforcement of the new guidance by the FDA has been uneven, but positioning the process validation to satisfy the new guidance requires the drug substance manufacturer to formally implement characterization and validation standards, just as a drug product manufacturer would be required to do.

Life-cycle management

The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. There should be a systematic approach to managing knowledge related to both drug substance and its manufacturing process throughout the lifecycle. This knowledge management should include but not be limited to process development activities, technology transfer activities to internal sites and contract manufacturers, process validation studies over the lifecycle of the drug substance, and change management activities.

Conclusion

The new ICH Q11 guidance represents the most recent example of the FDA’s commitment to the principles of QbD to define an integrated framework for implementing the principles of ICH Q6-Q10. Although the guidance does not mandate adopting ICH Q8, the considerations required to create a defensible control strategy require a much higher level of process understanding than the conventional approach of sample and test, once the foundation of product development. Defining the requirements is another example of where the FDA is going in terms of expectations for drug substance and drug product understanding. If effectively enforced, this can be a significant step forward, pushing the industry toward a QbD philosophy for process and product development.

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