Author: DR ANTHONY MELVIN CRASTO Ph.D

FDA reaches agreement with automatic external defibrillator manufacturer over quality control issues

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FDA reaches agreement with automatic external defibrillator manufacturer over quality control issues

Company must cease manufacturing until corrective action is taken 

U. S. District Judge Denise J. Casper entered a consent decree of permanent injunction yesterday between the U.S. and Philips North America LLC (doing business as Philips Medical Systems and Philips Healthcare) of Andover, Massachusetts, and two of the company’s officers, Carla Kriwet, business group leader for the Patient Care and Monitoring Solutions (PCMS) business group, and Ojas Buch, vice president, head of quality and regulatory for PCMS. The PCMS business group includes the Emergency Care and Resuscitation (ECR) business unit, which markets automatic external defibrillators (AEDs) and Q-CPR Meters. Continue reading.

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“DRUG REG AFFAIRS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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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FDA warns companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer

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As part of the U.S. Food and Drug Administration’s ongoing efforts to protect consumers from health fraud, the agency today issued warning letters to four companies illegally selling products online that claim to prevent, diagnose, treat, or cure cancer without evidence to support these outcomes. Selling these unapproved products with unsubstantiated therapeutic claims is not only a violation of the Federal Food, Drug and Cosmetic Act, but also can put patients at risk as these products have not been proven to be safe or effective. The deceptive marketing of unproven treatments may keep some patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.Continue reading .

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FDA takes unprecedented step toward more efficient global pharmaceutical manufacturing inspections 

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FDA takes unprecedented step toward more efficient global pharmaceutical manufacturing inspections 

 

The U.S. Food and Drug Administration has determined the agency will recognize eight European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements. The eight regulatory authorities found to be capable are those located in: Austria, Croatia, France, Italy, Malta, Spain, Sweden and the United Kingdom. Continue reading.

Statement from FDA Commissioner Scott Gottlieb, M.D., on newsteps to advance medical device innovation and help patients gain faster access to beneficial technologies

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Statement from FDA Commissioner Scott Gottlieb, M.D., on newsteps to advance medical device innovation and help patients gain faster access to beneficial technologies

Enabling patients and providers to have efficient access to new and innovative medical products that meet the FDA’s gold standard for safety and effectiveness is a core part of our mission. We’re advancing these goals as part of the Medical Innovation Access Plan that I announced earlier this year. While we’ve unveiled parts of that plan already, we’ll be releasing its full detail shortly. As one part of that effort, we’re announcing some additional steps we’re taking right now to promote beneficial medical device innovation. Continue reading.
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FDA warns Magellan Diagnostics of significant violations of the law as part of investigation into lead testing issues

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FDA warns Magellan Diagnostics of significant violations of the law as part of investigation into lead testing issues

Today the U.S. Food and Drug Administration issued a warning letter to Magellan Diagnostics Inc. for several violations of federal law, including marketing significantly modified versions of two of its blood lead testing systems without the FDA’s required clearance or approval and failing to submit medical device reports to the FDA after becoming aware of customer complaints involving discrepancies in blood lead test results. Continue reading.

Phytomenadione, Phytonadione, фитоменадион ,فيتوميناديون ,

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New Drug Approvals

Vitamin K1.png

ChemSpider 2D Image | Phylloquinone | C31H46O2

Phytomenadione,

PHYTONADIONE, Phylloquinone

Molecular Formula: C31H46O2
Molecular Weight: 450.707 g/mol
[R-[R*,R*-(E)]]-2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione
1,4-Naphthalenedione, 2-methyl-3-((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecenyl)-
2′,3′-trans-Vitamin K1
фитоменадион [Russian] [INN]
فيتوميناديون [Arabic] [INN]
2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]naphthalene-1,4-dione
 CAS 84-80-0[RN]
Antihemorrhagic vitamin
Aqua mephyton
AQUAMEPHYTON
Combinal K1
Kativ N
Kephton
Kinadion
K-Ject
KONAKION
Mono-kay
Phyllochinonum
Phylloquinone (8CI)
Optical Rotatory Power -0.28 ° Solv: 1,4-dioxane (123-91-1); Wavlen: 589.3 nm; Temp: 25 °CKarrer, P.; Helvetica Chimica Acta 1944, VOL 27, PG317-19

MASS

1H NMR

400 MHZ CDCL3

13C NMR

  1. Murahashi, Shun-ichi; European Journal of Organic Chemistry 2011, VOL2011(27), P5355-5365 
  2. Huang, Zhihong; Advanced Synthesis & Catalysis 2007, VOL349(4+5), PG539-545 

IR LIQ FILM

Phylloquinone is a family of phylloquinones that contains a ring of 2-methyl-1,4-naphthoquinone and an isoprenoid side chain. Members of this group of vitamin K 1 have only one double bond on the proximal isoprene unit. Rich sources of vitamin K 1 include green plants, algae, and photosynthetic…

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ICH Q11 Q and A Document

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Image result for ICH Q11

ICH Q11   Q and A Document


The topic of starting materials has been a vexed topic for some period. Indeed concerns relating to lack of clarity and issues pertaining to practical implementation led the EMA in Sept 2014 to publish a reflection paper—Reflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.(10) The paper sought to outline key issues as well as authority expectations; specific areas of interest identified included the following:

1.

Variance in interpretation between applicant and reviewer.

2.

The registration of short syntheses that employ complex custom-made starting materials.

3.

Lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy.

Image result for ICH Q11Image result for ICH Q11

While the consensus was that overall this provided a useful perspective of at least the EMA’s interpretation of ICH Q11(2) and requirements for starting material selection, further discussion was required to address this subject to the satisfaction of both industry and regulators.
In November 2016 ICH released a Q&A document pertaining to ICH Q11, the purpose of which is to clarify the expectations regarding the selection and justification of starting materials for drug substance manufacture. This has reached Step 2,(11) a consensus document released for public comment, the deadline being March 2017.
The document comprises a series of sections, beginning with an introduction. This makes clear that the focus of the Q&A document is on chemical entity drug substances, excluding Biologics at least in the sense of definition of starting materials.
Another important proposal made within the introduction is that API starting materials that have already been accepted by regulatory authorities (e.g., for use in authorized medicinal products) would not need to be rejustified against the ICH Q11 general principles or the recommendations included in this Q&A document, unless significant changes are made to the manufacturing processes and controls.
This is important as a concern may have been that criteria defined in the document would be retrospectively applied. It is though caviated, stating that a starting material accepted for one manufacturer’s process may not be considered acceptable for a different manufacturer’s process.
It also states that designation of starting materials should be based on process knowledge for the intended commercial process. It emphasizes that all of the general principles in ICH Q11 Section 5 should always be considered holistically, together with the clarifications in this Q&A document, rather than applying a single general principle or Q&A clarification in isolation. This was a thread central to the argumentation within the earlier EMA guideline.

The questions and answers are aligned to specific sections within the guideline, although all questions are focused specifically on Section 5—Selection of starting material and source material. There are 16 questions in total covering the following aspects:

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1.

Significant Structural Fragment: how should this be interpreted

2.

Impact on Impurity profile of final product: this relates to the guidance within Q11 to include all stages that impact on impurity profile of the drug substance. This seeks to clarify what level would be defined as impactful.

3.

Clarification of persistence

4.

How an applicant should determine which steps impact the profile of mutagenic impurities in the drug substance.

5.

Do all steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included in the process description?

6.

Clarification of the stated need to describe “enough” of the drug substance manufacturing

7.

Should all the ICH Q11 general principles be considered and met in selecting starting materials?

8.

Application of Q11 principles to telescoped processes

9.

Application of Q11 to linear and convergent syntheses

10.

Starting material specifications: key attributes

11.

Noncommercial starting materials

12.

Differences: Commercially available vs Custom Synthesis

13.

Requirements for justification of commercial availability

14.

Scope: postapproval change–preregistered starting materials

15.

Life cycle management

16.

Starting material Q11 vs Q7 definition: clarification that this is effectively the same

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It is beyond the scope of this review to examine the specific text associated with all 16 questions. In general though the position articulated throughout is pragmatic and also, in general, answers are clear and relatively concise.

Key points of note include

  • “Significant structural fragment”: the document highlights the frequent misconception that this means that a proposed starting material should be structurally similar to the drug substance. It makes clear that in fact the intent is simply 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.

  • Questions 5.2, 5.4, and 5.5 relate to mutagenic impurities. The answers provided should be useful in assisting an applicant in applying the risk based approach defined within ICH M7.(5)Prior to this there was a general misconception that a step that involved a mutagenic impurity needed to be part of the registered process. Such an assertion took no account of the highly reactive nature of such impurities and their propensity to be effectively purged.(12) The answer to question 5.2 makes clear the framework for defining the impact of an MI on the quality of the final drug substance, aligning this directly to M7 and the adoption of the widely applied 30% of the limit principle, i.e. prove levels in the final active drug substance are below 30% of the acceptable limit. The answer to question 5.4. provides a commentary of the actual practical steps involved in assessing the impact of an MI. Importantly within this it contextualizes the actual risk posed by low level MIs with the following important statement

    • “Such mutagenic impurities and by-products are usually present at much lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents, or intermediates from the same steps.”

In essence, provided any MI associated with a starting material is demonstrably controlled it is not necessary to register stages that simply employ the use of mutagenic reagents.

  • Another important point addressed within the document is ‘persistency.’ It seeks to make clear that even where an impurity associated with a starting material does impact on the quality of the drug substance that control can be defined at the stage of the starting material. A classic example would be a stereoisomer. General downstream processing would have little impact on levels. In many cases this has led to a view that the step where such an impurity might arise must form part of the registered process, i.e. the stage of introduction of chirality. This now makes clear that, provided this is effectively controlled within the starting material, registration of earlier stages is not required.

Again, the key concerns raised by the EMA reflection paper(10) are reflected on, i.e. registration of short syntheses that employ complex custom-made starting materials and a lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy. Arguably in that context the answer provided to question 5.6 is the most critical in the Q&A document.
Question 5.6 ICH Q11 states that “enough of the drug substance manufacturing process should be described in the application···” What considerations should an applicant apply in the selection of the proposed starting materials to ensure that enough of the drugs substance manufacturing process will be described in the process description in Section 3.2.S.2.2 of the application?

The response highlights several key aspects

Of primary importance is that the applicant must first evaluate which chemical transformation steps in the manufacturing process impact the impurity profile of the drug substance. With the clarification now provided in respect to MIs and “persistency” this should be more straightforward than previously was the case.

Another key point made is the need for an applicant to examine steps immediately upstream of those identified as critical and within those upstream to consider if:

  • They include a unit operation that has been added to the manufacturing process to control specific impurities that would otherwise impact the impurity profile of the drug substance.

The key point made here is that you cannot simply add multiple purification steps prior to a proposed starting material.

  • Tight control (e.g., within narrow parameter ranges) is required to prevent generation of impurities that would otherwise impact the impurity profile of the drug substance.

If either are the case then these should be included within the registered synthesis.

Perhaps the most contentious aspect of the response though is the caveat that if having conducted the assessment described and if based on this the result is that only a small number of chemical transformation steps need to be registered, the Q&A document articulates a need to include one or more additional steps. The reasons stated for this needing to be considered are

  • Due to the risk of contamination arising from a late starting material and the impact this would have on drug substance quality and

  • The risk of changes made to the route/process for the starting material impacting again on drug substance quality.

Many organizations will I’m sure challenge this, as it seems to suggest little or no control around quality of starting materials; in reality that is far from the case.
Ultimately does the response to this question and the overall document adequately address regulatory concerns, in particular those outlined EMA? Only time will tell, but overall this is a welcome development.
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References


  1. 1.Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities EMA/CHMP/ CVMP/ SWP/169430/ 2012,http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf.

  2. 2.ICH Q11 – Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)Q11http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf.

  3. 3.TeasdaleA.Regulatory Highlights Org. Process Res. Dev. 201519 ( 4494– 498DOI: 10.1021/acs.oprd.5b00085

  4. 5.Assessment and Control of Dna Reactive (Mutagenic)Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1) March 2017,http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_Step_4_31Mar2017.pdf.

  5. 8.HarveyJ.TeasdaleA.FleetwoodA.Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development Regul. Toxicol. Pharmacol. 201784116– 123,DOI: 10.1016/j.yrtph.2016.12.011

  6. 9.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’ (EMA/CHMP/CVMP/SWP/169430/ 2012) .http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf.

  7. 10.Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substanceshttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500175228.pdf.

  8. 11.ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) – questions and answershttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Q_A_Step_2.pdf.

  9. 12.TeasdaleA.Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate Control Org. Process Res. Dev. 201317221– 230DOI: 10.1021/op300268u

  10. 13.EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Usehttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/chapter_5.pdf.

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