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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Elemental Impurities

 regulatory, Uncategorized  Comments Off on Elemental Impurities
Jul 112018
 

Image result for elemental impurities

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 are based on modern analytical capabilities, replace the outdated tests in the deleted USP General Chapter 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.
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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.
Image result for elemental impurities
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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Practical Implementation of the Control of Elemental Impurities: EMA’s new Guideline Draft

 regulatory  Comments Off on Practical Implementation of the Control of Elemental Impurities: EMA’s new Guideline Draft
Jul 222016
 

 

One and a half year after its publication, the ICH Q3D guideline still raises many questions. The EMA has recently published a guideline draft aiming at clarifying the practical implementation of ICH Q3D. Read more here about what is expected in a marketing authorisation application or in an application for a CEP with regard to risk assessment and the control of elemental impurities in APIs and medicinal products.

http://www.gmp-compliance.org/enews_05481_Practical-Implementation-of-the-Control-of-Elemental-Impurities-EMA-s-new-Guideline-Draft_15339,15429,15332,S-WKS_n.html

The “ICH Q3D Guideline for Elemental Impurities” was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA’s Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).

In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.

On 12 July 2016, the draft of an EMA’s guideline entitled “Implementation strategy of ICH Q3D guideline” (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.

The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter “1. Different approaches to Risk Management” starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:

Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If – with this approach – the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.

Component Approach
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.

The chapter “2. Particulars for Intentionally Added Element(s)” deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.

The chapter “3. ASMF/CEP: dossier expectations and assessment strategy” explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:

1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.

2. The API manufacturer doesn’t perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won’t make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.

The guideline draft can be commented on until 12 August 2016.

///////////ICH Q3D, Control of Elemental Impurities,  EMA, control of elemental impurities in APIs

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Results of a Survey on ICH Q3D “Elemental Impurities”

 regulatory  Comments Off on Results of a Survey on ICH Q3D “Elemental Impurities”
Jun 022016
 

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

SEE

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

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

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

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

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

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

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

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

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

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

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

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

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

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ICH Q3D Implementation Working Group (IWG)—Training Modules

 regulatory, Uncategorized  Comments Off on ICH Q3D Implementation Working Group (IWG)—Training Modules
May 172016
 

ICH Q3D Implementation Working Group (IWG)—Training Modules


ICH Q3D is a complex guideline. The overall requirement in terms of control is clear—there are defined limits for some 24 elements, and levels of the elements described must be controlled within these limits in the final drug product. Simple. The complexity comes when defining how this is achieved. The guideline provides a series of options to evaluate risk and effect control, ranging from control in each individual component based on a fixed dose for the product of 10 g (Option 1) to simply testing the final product (Option 3). A detailed description of the options and when/how these are applied as part of a risk assessment is beyond the scope of this review; the point is that there are significant challenges in applying the guideline practically solely using the guideline for that purpose. This was recognized by the ICH Expert Working Group responsible for the guideline, resulting in the establishment immediately after step 4 of an Implementation Working Group. A key objective of the IWG was to develop training materials to assist implementation.
In February ICH finally published the long awaited training modules.(2) These modules, produced by the ICH Q3D implementation working group, cover both safety and quality aspects, the areas covered are listed below:

Module 0

This provides an overview of the modules. Included within this is a very useful flow diagram,Figure 1, highlighting the anticipated overall process from the risk assessment through to definition of control strategy.

Modules 1–3 Cover Toxicology Aspects

Module 1—Different Routes of Administration

Module 2—Justification of Levels Greater than Permissible Daily Exposure Limits

Module 3—Non ICH Elements

Modules 4–7 Cover Chemistry (Quality) Aspects

Module 4—Large Volume Parenterals

Module 5—Risk Assessment

Module 6—Control

Module 7—Calculation Options

Highlighting some key points, module 5, relating to risk assessments, discusses the key role of GMP in assessing risk—this is an important and a helpful point relating to API manufacture. It emphasizes the importance of:

1.

Design and qualification;

2.

Maintenance procedures.

However, it also focuses on the risk arising from manufacturing equipment, making a relatively generic statement over the often more chemically aggressive nature of API manufacturing procedures compared to drug product manufacturing. It even suggests monitoring the drug substance for potential impurities arising from manufacturing equipment (e.g., stainless steel—Cr, Mn, Mo, V, Ni). It is a pity that this risk is highlighted without also making the point that it would be expected that such risk would be addressed as part of GMP and form part of the process accommodation procedure rather than rely on screening to verify.

Rightly the module makes the point that a significant potential source of elemental impurities arises from the use of metal catalysts in the synthesis of drug substances, especially if used in the latter stages of synthesis. It also states that:

“Knowledge of potential elemental impurities in synthetic steps prior to the final drug substance may provide information that can assist in the preparation of the risk assessment.”

This is an interesting point and one that cuts to the heart of the uncertainties around practical implementation. While a valid point, it raises key questions such as how many steps prior to the API should be assessed? Clearly this will be process/product specific, but it is a very real question any risk assessment will have to tackle.
Another interesting point made in the module is the potential for “platform” risk assessments. This is the concept of a risk assessment applicable across a series of products. One such platform may be for example, oligonucleotides.(3) In such instances, where the manufacturing process in terms of reagent type, equipment, and process conditions are similar irrespective of the precise end product, it should be possible to conduct an assessment based on one process and for this to relevant/transposable to comparable processes.

Figure

Figure 1
Module 6—Control of Elemental Impurities—also provides useful advice emphasizing the importance of control across the product lifecycle. In the context of the manufacture of the API, this requires oversight and governance over changes to the process that may affect the risk assessment, e.g., change in catalyst load, and so forth. Such changes require a re-evaluation and possibly confirmatory testing. Another point emphasized in the module is that routine testing of Class 1 metals, i.e., arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb), is NOT required unless there is an identified risk. This is a very important and helpful point clearly reiterating the core principle of ICH Q3D that any control strategy should be based on the risk assessment. This is especially important as several regulatory queries have been reported asking for data for Class 1 and also Class 2A metals for APIs.

One area described in Module 6 is the concept of periodic testing. This is an area of potential concern and ambiguity. It states that:

“Where the risk assessment indicates that routine testing is considered unnecessary but some additional assurance is needed post approval, periodic testing of the drug product or one or more individual components may be proposed by the applicant and implemented upon acceptance by the regional regulatory authority.”

An example is provided relating to use of a Pt catalyst in the manufacture of the API, this being the final step used in the API synthesis. In the example detectable levels of Pt at ∼ 20% of the PDE are observed (below the 30% limit stated in ICH Q3D), based on this periodic testing being proposed. In the case study described this may seem sensible but how close to reality is such an example? In such a case would an applicant simply not specify Pt on the API specification? The worry is that the option for periodic testing may be blunt instrument and be something that is regularly requested.

USP Chapter ⟨232⟩

USP very recently announced(4) a series of revisions to USP Chapter ⟨232⟩, Elemental Impurities, the revisions made being intended to align the general chapter more closely to ICH Q3D. One of the most significant is the removal of the need to routinely screen for Class 1 metals as part of any analysis, the final sentence in the text outlined below being deleted.

If, by process monitoring and supply chain control, manufacturers can demonstrate compliance, then further testing may not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental Impurities—Procedures ⟨233⟩.

This is a welcome and important amendment; the previous requirement making little scientific sense, there being no actual evidence that Class 1 metals would be more prevalent, for example, where a platinum catalyst was used than in the absence of a catalyst. Such catalysts are not a source of class 1 metals.

Overall

Overall there are likely to be challenges/uncertainties associated with ICH Q3D leading up to and for some period after the effective date as the guideline beds in, but the crucial fact is that all of the evidence to date indicates it is unlikely that there will be a widespread impact caused by issues of excessive levels of any elemental impurity whereby effective control cannot be realized.
/////////ICH Q3D, Elemental Impurities, Procedures ⟨233⟩, Training Modules
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ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

 regulatory  Comments Off on ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities
Apr 072016
 

 

ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

Two general monographs of the European Pharmacopoeia have been revised and published for comment in the newest “Pharmeuropa” edition. Read more about what you will have to consider in future with regard to the control of elemental impurities in pharmaceutical preparations, APIs and excipients.

see

http://www.gmp-compliance.org/enews_05296_ICH-Q3D-implemented-in-the-European-Pharmacopoeia-Revision-of-Two-General-Monographs-with-Regard-to-Elemental-Impurities_15499,15332,S-AYL_n.html

In a press release dated 30 November 2015, the EDQM announced the revision of two general pharmacopoeial monographs: “Substances for pharmaceutical use” (2034) and “Pharmaceutical preparations” (2619). The decision was taken during the 153rd session of the European Pharmacopoeia Commission; the Commission follows its strategy for implementing the ICH Guideline Q3D “Guideline for Elemental Impurities” in the European Pharmacopoeia. A section “Elemental Impurities” has been added to both monographs which emphasizes that the provisions laid down in General Chapter 5.20 of the Pharmacopoeia (identical in wording with ICH Q3D) apply to the limits of metallic impurities and to their control. For pharmaceutical preparations and substances for pharmaceutical use outside the scope of Chapter 5.20 (e.g. unlicensed patient-specific preparations, herbal products, radiopharmaceuticals, etc.), the manufacturer is obliged to perform a risk assessment with regard to the limits of those impurities and – if necessary – to use validated analytical procedures for their determination. The principles to be applied for such a risk assessment arise from a press release from the EDQM dated 7 August 2015: it is expected that the provisions defined on the Guidelines ICH Q3D or ICH Q9 are followed. Lastly, according to this press release, the control strategy of elemental impurities as well as the substantial demonstration of suitability of the analytical methods used in the marketing authorisation dossier remains in the responsibility of the manufacturer.

The definition of “Substances for pharmaceutical use” in the monograph 2034 states: “Substances for pharmaceutical use are any organic or inorganic substances or excipients for the production of medicinal products for human or veterinary use. … Substances for pharmaceutical use may be used as such or as starting materials for subsequent formulation to prepare medicinal products. Depending on the formulation, certain substances may be used either as active substances or as excipients.”

The drafts of the two revised general monographs are accessible for free in the Journal “Pharmeuropa“, Edition 28/2. You only need to register and log in with your password. The comment deadline for both monograph drafts ends on 30 June 2016.

 

 

 

 

 

 

 

 

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Other reading

https://www.thermoscientific.com/content/dam/tfs/ATG/CMD/cmd-documents/ref/third/USP-Primer-eBook.pdf

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

http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Concept_Paper_ October_21_2014.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Business_Plan_ October_21_2014.pdf

///////ICH Q3D,  implemented,  European Pharmacopoeia, Revision, Two General Monographs,  Elemental Impurities

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