AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Elaboration of New USP General Chapter <1220> – Analytical Procedure Lifecycle – announced

 regulatory, USP  Comments Off on Elaboration of New USP General Chapter <1220> – Analytical Procedure Lifecycle – announced
Jul 222016
 

 

On June 24, 2016, the USP announced the elaboration of a new general chapter <1220> regarding life cycle management of analytical methods. Read more about the new general chapter  <1220> “The Analytical Procedure Lifecycle“.

SEE

http://www.gmp-compliance.org/enews_05438_Elaboration-of-New-USP-General-Chapter–1220—-Analytical-Procedure-Lifecycle—announced_15438,15608,Z-PDM_n.html

On June 24, 2016, the USP announced the elaboration of a new general chapter <1220> “The Analytical Procedure Lifecycle”. Input Deadline is July 29, 2016.

The suggested audience are drug product manufacturers, dietary supplement manufacturers, testing organizations, and drug product related regulatory agencies.

“An analytical procedure must be shown to be fit for its intended purpose. It is useful to consider the entire lifecycle of an analytical procedure when approaching development of the procedure, i.e. its design, development, qualification, and continued verification. The current concepts of validation, verification, and transfer of procedures address portions of the lifecycle but do not consider them holistically. This General Chapter intends to more fully address the entire procedure lifecycle and define concepts which may be useful.”

The approach is consistent with the concepts of Quality by Design (QbD) as described in ICH Guidelines Q8 (R2), 9, 10, and 11 and with the expected new ICH Guideline Q12 (Lifecycle Management).

Preliminary outline:
THE LIFECYCLE APPROACH

  • focal point: Analytical target profile (ATP), comparable to the Quality Target Product Profile (QTPP).

STAGE 1: PROCEDURE DESIGN, DEVELOPMENT, AND UNDERSTANDING

  • Procedure design and development,
  • Procedure understanding,
  • Preparing for qualification.

STAGE 2: PROCEDURE PERFORMANCE QUALIFICATION

STAGE 3: IMPLEMENTATION AND CONTINUED PROCEDURE PERFORMANCE VERIFICATION

  • Routine monitoring,
  • Analytical control strategy,
  • Knowledge management,
  • Change control.

Anticipated proposed design phase activities:

Two Stimuli articles are scheduled for PF 42(5) [Sep.–Oct. 2016]:

  • Analytical Target Profile: Structure and Application throughout the Analytical Lifecycle,
  • Analytical Control Strategy.

Two stimuli articles have already been published:

  • Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification. PF 39(5) [Sep.–Oct. 2013],
  • Fitness for Use: Decision Rules and Target Measurement Uncertainty. PF 42(2) [Mar.–Apr. 2016].

Additionally, the USP proposed a revision of general chapter <1225> “Validation of compendial procedures” in PF 42(2) [March-April 2016].
This chapter is being revised to incorporate a section on “Lifecycle Management of Analytical Procedures”. The revision is an attempt to better align the validation concept with the recently (July 2015) issued FDA guidance “Analytical Procedures and Methods Validation for Drugs and Biologics”, which also includes a section on “Life Cycle Management of Analytical Procedures”.

Estimated proposal for the new general chapter <1220> “The Analytical Procedure Lifecycle” is PF 43(1) [Jan.–Feb. 2017].

Furthermore, an USP and ECA Joint Conference and Workshop on Lifecycle Approach of Analytical Procedures will be held November 8-9, 2016 in Prague, Czech Republic.

For more information please visit the USP website – Notices- General Chapter Prospectus – The Analytical Procedure Lifecycle.

 

 

//////////The Analytical Procedure Lifecycle, USP, chapter <1220>

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Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages

 companies, INDIA, MANUFACTURING, new drugs, PRECLINICAL, PROCESS, regulatory  Comments Off on Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API’s in early Clinical Drug Development Stages
Jul 162016
 

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Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability  to  design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100’s of kilos of in a relatively short time.

Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………

WEBSITE………. https://sreenilabs.com/

INTRODUCTION

Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.

The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.

They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or  by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes

Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands,  heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks.  They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.

Some of the compounds prepared by Sreeni labs;

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See presentation below

LINK ON SLIDESHARE

Managing Director at Sreeni Labs Private Limited

 

Few Case Studies : Source SEEENI LABS

QUOTE………….

One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.

 

One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn’t deliver even a milligram in four months with 3 FTEs.

 

One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.

 

One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.

 

Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers.  We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.

 

One West coast customer approached us through a common friend’s reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO  for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide,  palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route  in less than three months time. You pay us only after we deliver 15 kg material. The customer didn’t want to take a chance with their timeline as they didn’t work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.

 

One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time.  

UNQUOTE…………

 

The man behind Seeni labs is Dr.Sreenivasa  Reddy Mundla

Sreenivasa Reddy

Dr. Sreenivasa Reddy Mundla

Managing Director at Sreeni Labs Private Limited

Sreeni Labs Private Limited

Road No:12, Plot No:24,25,26

  • IDA, Nacharam
    Hyderabad, 500076
    Telangana State, India

Links

https://sreenilabs.com/

LINKEDIN https://in.linkedin.com/in/sreenivasa-reddy-10b5876

FACEBOOK https://www.facebook.com/sreenivasa.mundla

RESEARCHGATE https://www.researchgate.net/profile/Sreenivasa_Mundla/info

EMAIL mundlasr@hotmail.com,  Info@sreenilabs.com, Sreeni@sreenilabs.com

Dr. Sreenivasa Mundla Reddy

Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook’s lab. From 1994 to 2000,  worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. 

In 2007  resigned to his  job and founded Sreeni Labs based in Hyderabad, Telangana, India  and started working with various global customers and solving various challenging synthesis problems. 
The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100’s of kg scale.
 

They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.

Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects

Experience

Founder & Managing Director

Sreeni Labs Private Limited

August 2007 – Present (8 years 11 months)

Sreeni Labs Profile

Sreeni Labs Profile

View On SlideShare

Principal Research Scientist

Eli Lilly and Company

March 2001 – August 2007 (6 years 6 months)

Senior Research Scientist

Procter & Gamble

July 1994 – February 2001 (6 years 8 months)

Education

University of Hyderabad

Doctor of Philosophy (Ph.D.), 
1986 – 1992

 

PUBLICATIONS

Article: Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration

Jianye Zhang · Zhiqian Dong · Sreenivasa Reddy Mundla · X Eric Hu · William Seibel ·Ruben Papoian · Krzysztof Palczewski · Marcin Golczak

Article: ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative

Sreenivasa Mundla

Aug 2010 · ChemInform

Article: Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

Hong-yu Li · William T. McMillen · Charles R. Heap · Denis J. McCann · Lei Yan · Robert M. Campbell · Sreenivasa R. Mundla · Chi-Hsin R. King · Elizabeth A. Dierks · Bryan D. Anderson · Karen S. Britt · Karen L. Huss

Apr 2008 · Journal of Medicinal Chemistry

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Feb 2008 · ChemInform

Article: ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions

Hong-yu Li · Yan Wang · William T. McMillen · Arindam Chatterjee · John E. Toth ·Sreenivasa R. Mundla · Matthew Voss · Robert D. Boyer · J. Scott Sawyer

Nov 2007 · Tetrahedron

Article: Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Hong-yu Li · Yan Wang · Charles R Heap · Chi-Hsin R King · Sreenivasa R Mundla · Matthew Voss · David K Clawson · Lei Yan · Robert M Campbell · Bryan D Anderson · Jill R Wagner ·Karen Britt · Ku X Lu · William T McMillen · Jonathan M Yingling

Apr 2006 · Journal of Medicinal Chemistry

Read full-textSource

Article: Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system

Hui Cao · Sreenivasa R. Mundla · James M. Cook

Aug 2003 · Tetrahedron Letters

Article: ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes

Sreenivasa R. Mundla

Nov 2000 · ChemInform

Article: ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines

Read at

[LINK]

Patents by Inventor Dr. Sreenivasa Reddy Mundla

  • Patent number: 7872020

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Grant

    Filed: June 29, 2006

    Date of Patent: January 18, 2011

    Assignee: Eli Lilly and Company

    Inventor: Sreenivasa Reddy Mundla

  • Publication number: 20100120854

    Abstract: The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.

    Type: Application

    Filed: June 29, 2006

    Publication date: May 13, 2010

    Applicant: ELI LILLY AND COMPANY

    Inventor: Sreenivasa Reddy Mundla

  • Patent number: 6066740

    Abstract: The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.

    Type: Grant

    Filed: November 25, 1997

    Date of Patent: May 23, 2000

    Assignee: The Procter & Gamble Company

    Inventors: Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth

TGF-β inhibitors

US 7872020 B2

Sreenivasa Reddy Mundla

The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.

Figure US07872020-20110118-C00002

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Figure US07872020-20110118-C00008

Galunisertib

1H NMR (CDCl3): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16

ABOVE MOLECULE IS

https://newdrugapprovals.org/2016/05/04/galunisertib/

Galunisertib

Phase III

LY-2157299

CAS No.700874-72-2

 

 

READ MY PRESENTATION ON

Accelerating Generic Approvals, see how you can accelerate your drug development programme

Accelerating Generic Approvals by Dr Anthony Crasto

KEYWORDS   Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India,  new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3,  API, drugs, medicines

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EDQM announces revision of general chapter Monocyte Activation Test (2.6.30)

 regulatory  Comments Off on EDQM announces revision of general chapter Monocyte Activation Test (2.6.30)
Jul 142016
 

On 23 June, the EDQM in Strasbourg announced the revision of the pharmacopoeial general chapter 2.6.30 on Monocyte Activation Test.

see  http://www.gmp-compliance.org/enews_05440_EDQM-announces-revision-of-general-chapter-Monocyte-Activation-Test–2.6.30-_15500,15298,15853,15541,Z-MLM_n.html

During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.

Last week, the EDQM published the information that  during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).

It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.

The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.

The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.

For more information, please see the  EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.

In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.

During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.

Last week, the EDQM published the information that  during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).

It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.

The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.

The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.

For more information, please see the  EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.

In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.

/////Monocyte Activation Test

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Drafts of revised USP plastic packaging chapters <661.1> and <661.2>: removal of the biological reactivity test for oral and topical dosage forms

 regulatory  Comments Off on Drafts of revised USP plastic packaging chapters <661.1> and <661.2>: removal of the biological reactivity test for oral and topical dosage forms
Jul 142016
 

In a recent Pharmacopeial Forum two revised USP general chapters have been published for comment. With these drafts, the USP expert committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.

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http://www.gmp-compliance.org/enews_05453_Drafts-of-revised-USP-plastic-packaging-chapters–661.1–and–661.2–removal-of-the-biological-reactivity-test-for-oral-and-topical-dosage-forms_15493,15615,Z-PKM_n.html

 

In Pharmacopeial Forum 42(4) [Jun-Jul 2016] drafts of two revised USP general chapters <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use have been published for comment. Deadline for comments is September 30, 2016. With these drafts, the USP General Chapters – Packaging and Distribution Expert Committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms.

The Expert Committee is removing the requirement for <87> testing at this time, while the effort to revise the general chapters <87> and Biological Reactivity Tests, In Vivo <88> proceeds. Depending on the revisions of <87> and <88> the two packaging chapters may be revised to align with those chapters.

The new requirement (since May 2016) for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms has been highly discussed, since this testing is not required for the mentioned dosage forms according to EMA guideline on plastic immediate packaging materials (December 2005) and US FDA container closure guidance (May 1999). In case of oral and topical dosage forms both guidances require “only” compliance to food regulations (EU: regulation 10/2011, US: indirect food additives guidelines) or, if applicable, (preferably) to pharmacopoeial monographs (if the material or system is described in a pharmacopoeial chapter).

The principle of these two guidances is that materials considered safe for food contact are also safe for topical and oral dosage form packaging systems.

The new requirement (Biological Reactivity Tests, In Vitro) could have led to delays in releasing new oral or topical products on the market. Additionally, one might have had to re-evaluate already existing oral and topical products packaging systems on the market. Therefore, the present decision to revise the two packaging chapters regarding the requirement for <87>Biological Reactivity Tests, In Vitro seems to be justified.

Furthermore, the Expert Committee is proposing the addition of four new polymers [polyamide 6, polycarbonate, poly(ethylene-vinyl acetate), and polyvinyl chloride, plasticized] with test methods and specifications to general chapter <661.1>. To support the addition of these new polymers, polymer descriptions have been added to Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact <1661>, which appeared in PF 42(3) [May–June 2016].

In addition, the test for Spectral Transmission in Containers—Performance Testing <671> is being moved into general chapter <661.2> as requirement for light resistant containers.

On the basis of comments received, the scope of both chapters was revised for clarification.

After registration on the USP Pharmacopeial Forum website you can read the complete drafts of the two general chapters <661.1> and <661.2>.

 

Frequently Asked Questions: Plastic Materials of Construction <661.1> and Plastic Packaging Systems for Pharmaceutical Use <661.2>

  1. How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?
  2. If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?
  3. If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?
  4. Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?

  1. How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?

    In order to market a drug product, defined as a dosage form plus its associated packaging system, the product must be evaluated for its suitability for use by the relevant regulatory authority. The purpose of <661.1> is to increase the likelihood that a packaging system will be suited for use by providing data about its material(s) of construction, whereas the purpose of <661.2> is to establish that the packaging system is suited for use. Because suitability for use has already been established for marketed products via regulatory review, <661.1> and <661.2> testing has no additional value in terms of establishing suitability for use. Thus, a packaging system and its materials of construction that have been evaluated by a regulatory authority and are used with a marketed dosage form are considered to already meet the requirements of <661.2> and <661.1> (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

     

  2. If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?

    If a packaging system (and its materials of construction) that is used with one marketed dosage form is used with a second, compositionally similar dosage form, and if the conditions of use are similar for the two dosage forms, neither <661.1> nor <661.2> testing is required. This is because the information used to establish the suitability for use with the approved product is relevant to and is typically sufficient for establishing the suitability for use with the new product.

    If the new drug product is compositionally different from the approved product, and/or the conditions of use are different, then <661.1> testing would not be required. This is because generally, <661.1> testing is not dependent on the dosage form composition or the conditions of use.

    The exception to this statement is when a packaging system for a marketed “low-risk” dosage form is used for a new “high-risk” dosage form. A dramatic change in the nature of the dosage form would require <661.1> testing. This is because <661.1> testing of materials used with “high-risk” dosage forms is more extensive than <661.1> testing of materials used with “low-risk” dosage forms. In this scenario, those tests that are required for both low- and high-risk dosage forms do not need to be repeated (for example, Identity, Physicochemical Tests, Extractable Metals, and <87> Biological Reactivity Tests, In Vitro). Those tests that are unique to the high-risk dosage forms (e.g., <88> Biological Reactivity Tests, In Vivo as appropriate and Plastic Additives) would need to be performed.

    A similar analysis is true for <661.2> testing of the packaging system. Biological Reactivity and Physicochemical Tests are not specifically linked to a dosage form or conditions of contact, thus the packaging system would not need to be tested for these attributes regardless of any differences in the composition or conditions of use between the approved and new drug products. However, as the generation and toxicological safety assessment of an extractables profile is influenced by the composition of the dosage form and the conditions of use, it may be necessary to perform the Chemical Safety Assessment (extractables profiling and toxicological safety) in <661.2>. Under <661.2>, any decision not to perform this Chemical Safety Assessment would need to be justified on a case-by-case basis.

    When a packaging system for a marketed “high-risk” dosage form is used for a new “low-risk” dosage form, <661.1> and <661.2> testing is not necessary. In this case, whatever information was used to establish the suitability for use with the “high-risk” dosage form would also establish the suitability for use with the “low-risk” dosage form, as the “high-risk” information would generally represent a worst case scenario for the “low-risk” situation (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

     

  3. If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?

    As all materials of construction are required to meet <661.1>, it is expected that the new, different material would have to have been tested per <661.1>. Note that the new material would not be one of the legacy materials whose <661.1> compliance is “covered” by the fact that the product is being marketed.

    Use of a new and different material of construction in a packaging system can reasonably be anticipated to have an effect on the suitability for use of that packaging system. Thus, the new packaging system should be tested per <661.2>.

    Nevertheless, neither <661.1> nor <661.2> is intended to establish prescriptive requirements associated with exercising change control. Organizations are responsible for establishing their own change control practices, subject to approval by the appropriate regulatory authority. It is expected that those change control practices that do not specifically utilize <661.1> and <661.2> will include a justification for such practices, specifically focusing on the potential effect(s) that the change may have on user safety and product quality (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

    Table 1. Guidance for Situations where <661.1> and <661.2> Testing would be Applicable

    Situation Required Testing
    General Situation Specific Circumstances <661.1> <661.2>
    Packaging system used with a currently marketed pharmaceutical product No No
    New packaging system that has not gained regulatory approval for use with a to-be-marketed pharmaceutical product Yes Yes
    Changes to a packaging system used with a currently marketed pharmaceutical product A new material is introduced into the packaging system Yes (for the new material) Yes
    A material of construction in the packaging system is changed in either composition or process Yes (for the changed material) Yes
    The packaging system is changed, in either composition or process, in a manner that does not involve a change in its materials or to its materials (for example, changing the thicknesses of individual layers in a multi-layered film) No Yes
    Packaging system used with a currently marketed pharmaceutical product is to be applied to a different pharmaceutical product Dosage form and conditions of use are similar for the current and different pharmaceutical products No No
    Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “high risk” to “low risk” dosage form) No No
    Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “low risk” to “high risk” dosage form) Yes Yes

    Note: The provisions in <661.2> for packaging systems must be met for components whose testing has been deemed to be necessary.

     

  4. Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?

    In general, the amount and type of testing required to verify the suitability of packaging systems and their materials of construction should be consistent with the risk that the system or material could be unsuitable. In addition, the risk that packaging systems would be unsuited for use for solid oral dosage forms is lower than the risk associated with other dosage forms. Recognizing these generalizations, <661.1> has different testing requirements and/or specifications for these two groups of dosage forms. Because some of the tests required in <661.1> are applicable regardless of dosage form (for example, Identity, Physicochemical Tests, and Extractable Metals), such tests are applied with no difference to both groups of dosage forms. Although both groups of dosage forms are required to address Biological Reactivity, <661.1> requires only Biological Reactivity Tests, In Vitro <87> for oral and topical dosage forms while requiring both Biological Reactivity Tests, In Vitro <87> and Biological Reactivity Tests, In Vivo <88> (as applicable) for all other dosage forms. Both groups are required to address Plastic Additives, but solid oral dosage forms address this aspect by making proper reference to FDA’s Indirect Food Additive regulations while the other dosage forms address this issue by specified Plastic Additives testing.

    A cornerstone of suitability for use assessment of packaging systems and their materials of construction is the concept of orthogonal assessment. This is because individual means of assessment are generally insufficiently robust or broad enough in scope to provide rigorous and complete assessments on their own. Thus orthogonal assessments are performed to essentially “fill in the gaps” in the individual assessments.

Q: What types of “plastic packaging systems” are used in the pharmaceutical industry?

A: Plastic packaging systems for pharmaceutical use include bags, bottles, vials, cartridges, metered-dose inhalers, prefillable syringes, pouches and closures for capsules and tablets. Plastic materials commonly used in these systems include polyethylene, polypropylene, polyolefins, and polyvinyl chloride, among others.

Plastic packaging systems can include—not only the container that holds a particular drug product—but also gaskets, rubber stoppers, tubing and other components that may be part of the overall system used to store and/or deliver a drug to the patient.

Q: What are the key quality considerations for manufacturers of plastic packaging systems for drug products?

A: As drug products are manufactured, packaged, and stored, they come into direct contact with packaging systems and their plastic materials of construction. Such contact may result in interactions between the drug product and its packaging system. The packaging systems must protect and be compatible with drug products and not compromise their stability, efficacy or safety. In turn, the ingredients of a drug product should not be absorbed onto the surface or migrate into the body of the plastic packaging system.

The use of well-characterized plastic materials of construction and the appropriate testing of packaging systems help to determine if adverse interactions are taking place. Manufacturers should be able to provide a rationale for using a particular raw material of a packaging system and characterize that material to know what can possibly come out of it (e.g., additives, extractable  metals). This is key to determining potential interactions with a drug product.

Q: What are extractables and leachables?

A: Extractables are organic and inorganic chemical compounds that can be extracted from packaging material under laboratory conditions. They can be released from a pharmaceutical packaging/delivery system, a packaging component or a packaging material of construction. Depending on the specific purpose of a particular extraction study, laboratory conditions (e.g., solvent, temperature) may accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form. Extractables themselves (or substances derived from extractables) have the potential to leach into a drug product under normal conditions or storage and use and, thus, become leachables.

Leachables are extractables derived from drug packaging or delivery systems that may migrate into the drug product over the course of a drug product’s shelf life. Leachables can affect the stability and efficacy of the drug product, and in some extreme cases, introduce some patient safety risks.

Q: How can USP help?

A: The U.S. Pharmacopeial Convention (USP) is a nonprofit scientific organization that develops and revises public standards that help promote global drug quality. USP’s standards encompass drug substances, excipients, drug products and their delivery and packaging systems. These standards are available for use by industry, academia, regulators, healthcare professionals and other stakeholders.

USP’s published official standards—in the form of specifications for identity, strength, quality and purity in drug product, drug substance and excipient monographs as well as information and procedures in general chapters—appear in the compendia, U.S. Pharmacopeia—National Formulary (USP–NF).

Q: What USP standards are available to support work with plastic packaging systems, as well as extractables and leachables?

A: USP has developed the following standards specifically for plastic packaging systems:

  • General Chapter <661> Plastic Packaging Systems and their Materials of Construction: Testing rationale for plastic materials of construction and packaging systems used in the pharmaceutical industry. The use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suitable for its intended use since properties and characteristics of the materials can be matched to the performance requirements of the packaging system. (Current official standard, published in USP 38–NF 33.)
  • General Chapter <661.1> Plastic Materials of Construction: Tests, procedures and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems. Proper characterization of materials of construction facilitates the identification of and use of appropriate materials for pharmaceutical packaging systems. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
  • General Chapter <661.2> Plastic Packaging Systems for Pharmaceutical Use: Safety aspects of a drug product’s packaging system based on appropriate chemical assessments, includes performing extractables testing, leachables testing, and toxicology assessment. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
  • General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and execution of an extractables assessment for pharmaceutical packaging and delivery systems. Establishes critical dimensions of an extractables assessment and discusses practical and technical aspects of each. Also examines critical dimensions of an extraction study—laboratory generation of the extract (extraction) and testing the extract (characterization). (Current official standard, published in USP 38–NF 33, S1.)
  • General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and implementation of assessments for drug-product leachables derived from pharmaceutical packaging and delivery systems. Covers: 1) the requirement for leachables studies; 2) fundamental concepts for leachables studies; 3) the basis of thresholds for leachables and general guidance and application of these thresholds; 4) design and implementation of leachables studies; 5) leachables method development and validation; 6) correlation of results from extractables assessment and routine extractables testing with leachables studies; and 7) establishment of leachables specification including acceptance criteria. (Current official standard, published in USP 38–NF 33, S1.)

*This chapter is for informational purposes, it does not establish specific conditions, analytical methods, specifications, or acceptance criteria for any particular dosage forms or packaging system or drug product combination. The principles and best practices outlined in this general chapter represent a unified interpretation of sound science and are applicable to situations in which extractables or leachables assessment is required for pharmaceutical application. 

Q: Does USP have plans to develop future standards for plastic packaging systems?

A: Yes, USP is currently developing a brand new chapter <661.3> Plastic Materials for Pharmaceutical Manufacturing Systems which will cover plastic components and systems used in the manufacturing of a drug products. The chapter is scheduled to be published for public review and comment in Pharmacopeial Forum 42 (3) May 2016.

In addition, we will be hosting a workshop June 20–21 on Material Biocompatibility and Standard for Plastic Manufacturing Systems/Components at our facility in Rockville, MD.

We encourage all interested parties to take advantage of these two new resources to learn more and contribute to the development of new USP standards for drug packaging systems.

//////////////////Drafts, revised USP,  plastic packaging chapters <661.1> and <661.2>,  removal of the biological reactivity test for oral and topical dosage forms

 

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EMA reviews Medicines manufactured at U.S. Company

 regulatory  Comments Off on EMA reviews Medicines manufactured at U.S. Company
Jul 142016
 

Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.

The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).

Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).

This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).

EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.

There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.

Source: EMA Press Release

Pharmaceutics International Inc., USA

/////////// EMA,  Medicines,  manufactured, U.S. Company, Pharmaceutics International Inc., USA

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ECA Guide on Visual Inspection: updated version for all participants of the Particles event

 regulatory  Comments Off on ECA Guide on Visual Inspection: updated version for all participants of the Particles event
Jul 072016
 

 

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016 will receive a copy for free. Read more.

see

http://www.gmp-compliance.org/eca_mitt_05360_15266,15265,Z-PEM_n.html

The advisory board of the ECA Visual Inspection Group has worked on an update of its visual inspection guide. All participants of the ECA Conference Particles in Parenterals 2016, 28-29 September 2016 in Barcelona will receive a copy for free.

The paper, which is much rather supposed to be a reference than a strict requirement, covers Manual and Automated Inspection issues including qualification, validation and revalidation in the following chapters:

  • Manual inspection
  • Automated inspection
  • Inspection of lyophilized product
  • Defect Classes
  • Evaluation of defect classes and trending
  • Batch release
  • Concerns regarding distributed product

The chapter on manual inspection has been extended to also address semi-automated inspection. The chapter on batch release now contains more information and explanation on AQL testing.

More information can also be found on the group’s webpage.

 

//////////ECA Guide, Visual Inspection,  updated version, Particles event

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FDA issues new Draft Guidance on Elemental Impurities

 regulatory  Comments Off on FDA issues new Draft Guidance on Elemental Impurities
Jul 072016
 

The recently issued FDA Guideline on Elemental Impurities as a draft describes the procedure for controlling elemental impurities for medicinal products with and without official USP monograph. Read in what cases the FDA expects the fulfilment of the requirements of the Guideline ICH Q3D respectively of the general USP Chapter <232> und <233>.

see

http://www.gmp-compliance.org/enews_05465_FDA-issues-new-Draft-Guidance-on-Elemental-Impurities_15332,S-AYL_n.html

The ICH Q3D “Guideline for Elemental Impurities” was issued in December 2014 and recommended for adoption in the regulations portfolio of the ICH regions Europe, USA and Japan according to the ICH step-by-step procedure (Step 5). With the publication of the “ICH guideline Q3D on elemental impurities” (EMA/CHMP/ICH/353369/2013) in August 2015 the European Medicines Agency (EMA) implemented this step and determined June 2016 (for medicinal products to be newly approved) and December 2017 (for already approved medicinal products) as the dates for the Guideline to come into effect. The FDA took over the ICH Q3D Guideline in September 2015.

On 30 June 2016 the FDA Guidance for Industry “Elemental Impurities in Drug Products” was issued as a draft and is now open for comments for a period of 60 days.

The requirements of the Guidance apply to

  • New compendial and noncompendial NDA or ANDA drug products
  • Drug products not approved under an NDA or ANDA – as, e.g., compendial and noncompendial nonprescription OTC products.

Compendial medicinal products are generally supposed to fulfil the requirements defined in the general USP Chapters <232> und <233>. However, in the following cases the provisions of ICH Q3D have to be met:

  • For noncompendial drug products,
  • For metallic impurities listed only in ICH Q3D but not in the general USP Chapters <232> and <233>.

Correspondingly these provisions do also apply for changes to approved medicinal products, made with the goal to fulfil the requirements of the chapters <232> and <233> respectively of ICH Q3D. For compendial medicinal products the result of the change must be the compliance with <232> and <233>, noncompendial products have to comply with the provisions of ICH Q3D.

The FDA generally considers these kind of changes as low risk with regard to negative effects on identity, strength, quality, purity or potency. For that reason they are not subject to the CBE change procedure and can be reported to the FDA as part of the annual report.

The general USP Chapter <232> only comprises the PDE values of 15 elements, while ICH Q3D covers 24 elements. Otherwise both chapters were adapted to ICH Q3D and issued in the second supplementary volume of USP 38-NF 33 on 1 December 2015. However, both chapters can only be applied to compendial products starting on 1 January 2018 – the date mentioned in the General Notices 5.60.30 “Elemental Impurities in USP Drug Products and Dietary Supplements”. This is nearly the date (December 2017) determined for the application of ICH Q3D respectively the European Guideline (EMA/CHMP/ICH 353369/2013).

///////////FDA, Draft Guidance, Elemental Impurities

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Annex 16: How a QP should handle unexpected Deviations

 regulatory  Comments Off on Annex 16: How a QP should handle unexpected Deviations
Jun 302016
 

In a recent blog of the MHRA, the inspectorate looks at one aspect of the new Annex 16 – the handling of unexpected deviations.

see http://www.gmp-compliance.org/enews_05428_Annex-16-How-a-QP-should-handle-unexpected-Deviations_15432,15354,15367,Z-QAMPP_n.html

In a recent blog of the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), the inspectorate looks at one aspect of the new Annex 16 – the handling of unexpected deviations.

Before Annex 16 was revised, the handling of minor deviations from defined processes was discussed in the European Medicines Agency’s “reflection paper” EMEA/INS/GMP/227075/2008. However, the status of this paper was not always clear, and its use was not consistently applied. Now section 3 of the new Annex 16 provides guidance on when a Qualified Person (QP) may consider confirming compliance or certifying a batch where an unexpected deviation (concerning the manufacturing process and/or the analytical control methods) from the MA and/or GMP has occurred.

Pre-requisites

Before a QP releases a batch these pre-requisites need to be considered:

  • All registered specifications must be met! This includes specifications for active substances, excipients, packaging materials and medicinal products with all defined in-process, bulk and finished product specifications. If any registered specification is not met, the QP must not release the batch.
  • Only unexpected deviations fall under the scope of section 3. That does also mean that repeated deviations cannot be accepted for certification, because they no longer meet the “unexpected” criteria.
  • The deviation must be thoroughly investigated, the root cause determined and the necessary actions defined.
  • A risk management process should be used to determine the impact on quality, safety and efficacy.

Quality Management System

Quality Management System failures are not covered by this section. But the quality management system of the manufacturer should maintain a record of which batches have been certified under the respective provisions. And it should also be considered in the management review and annual product quality reviews.

Notification of the Authorities

If the handling of the deviation is in accordance with the Annex 16 restrictions, the competent authority does not need to be informed (see also Chapter 8 of the EU Guide). But manufacturers and importers are required to notify competent authorities of quality problems and non-compliance affecting the Marketing Authorisation (MA).

Please also see the MHRA Inspectorate’s blog for more detailed information.

 

//////Annex 16, QP, unexpected Deviations, mhra

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FDA publishes Technical Guide on Quality Metrics

 regulatory  Comments Off on FDA publishes Technical Guide on Quality Metrics
Jun 302016
 

 

The FDA has published a supplementing Guide on Quality Metrics. This is a very unusual step as the contents of the guide are planned to be integrated into the Guideline on Quality Metrics which hasn’t been finalised yet. Read more about the Technical Quality Metrics Guide.

see http://www.gmp-compliance.org/enews_05437_FDA-publishes-Technical-Guide-on-Quality-Metrics_15515,S-QSB_n.html

The FDA has published a supplementing Guide on Quality Metrics. This is a very unusual step as the contents of the guide are planned to be integrated into the Guideline on Quality Metrics which hasn’t been finalised yet.

The so-called FDA Quality Metrics Technical Conformance Guide should supplement the Guidance for Industry: Request for Quality Metrics published on 28 July 2015 which is currently still in the draft version. We have recently published a GMP News about a Quality Metrics Case Study at Aenova regarding a possible implementation. Now, the Technical Guide defines how the industry should submit Quality Metrics to the FDA. Technical standards and fields are defined. Basically, the FDA is oriented towards the data standards which are already established in other areas. FDA‘s so-called Study Data Technical Conformance Guide serves as a basis. Largely widespread in the industry, the XML format is used by the FDA and other authorities for the exchange of data and the submission of data within the marketing authorisation procedure (e.g. for eCTD).

Composed of 10 pages, the Guide primarily provides a definition of the variables necessary for the submission of Quality Metrics. The last page of the Guide refers to “Data Validation Rules”. Data Validation is defined as “a process that attempts to ensure that submitted data are both compliant and useful”. It should be ensured that the data are submitted in accordance with the required standard. The FDA recognises that the standardisation of data doesn’t ensure the quality of data, but it helps verify certain aspects of data quality thanks to automated checks. When finalising the Guidance for Industry on Quality Metrics, the FDA also wants to set validation requirements on the quality of data in the guideline and thus achieve that companies first perform a validation of their metrics before they submit them.

Source: FDA Quality Metrics Technical Conformance Guide

 

Figure 1: Types of images quality metrics.

////////

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ECA Visual Inspection Groups works on new FAQ Document

 regulatory  Comments Off on ECA Visual Inspection Groups works on new FAQ Document
Jun 232016
 

The advisory board of ECA’s Interest Group for Visual Inspection is working on a revision of a document with frequently asked questions with regard to visual inspection of parenterals.

see

http://www.gmp-compliance.org/enews_05379_ECA-Visual-Inspection-Groups-works-on-new-FAQ-Document_15266,15265,15221,15160,Z-PEM_n.htmlregard to visual inspection of parenterals.

 

The webpage of ECA’s Interest Group for Visual Inspection contains several sources for giving advice in the field of visual inspection of parenterals. Besides the practical guidance paper, it contains an online discussion forum and a document with frequently asked questions. It has become clear though, that many of the questions in the forum recur and that these questions have already been answered in the FAQ document. It was therefore decided to restructure the FAQ document:  the questions will now be sorted by topic to make the document easier to read. Also, in a group survey in February 2016 everybody was asked to send additional questions. The advisory board is now working on selected new questions which will be added to the restructured questions & answers document. The revised document will contain the following elements:

  • Manual inspection
  • Automated inspection
  • Qualification/Validation
  • Test sets
  • Requalification
  • AQL Testing
  • Defect categorisation
  • Special products
  • Regulatory affairs

It is planned to finish the document in summer 2016, but at the latest during a face-to-face meeting at the next group event in September 2016 in Barcelona. It will be made available to all group members afterwards.

 

//////////ECA Visual Inspection Groups,  FAQ Document, visual inspection of parenterals,

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