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Uncategorized | BioQuality.biz - Part 2

FDA Approves Perjeta (pertuzumab), with conditions

FDA has approved Genentech’s humanized monoclonal antibody Perjeta (pertuzumab), a new anti-HER2 therapy, to treat patients with HER2-positive late-stage (metastatic) breast cancer. Perjeta was reviewed under the agency’s priority review program, which provides for an expedited six-month review of drugs that may offer major advances in treatment.

However, there are production issues that potentially could affect the long-term supply of the drug, and FDA limited its approval to drug product that has not been affected by those issues. Genentech, has, of course, committed to take steps designed to resolve these production issues in a timely manner.

The issue, according to Patrick Y. Yang, Ph.D., Genentech’s head, Pharma Global Technical Operations is related to……… Read the rest in our June weekly issue01; to subscribe: http://bioquality.biz/newsletter.htm


Soluble tungsten in syringes seen as possible root cause of unwanted epo immunogenicity

Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity, Pharm Res. 2012 Jun;29(6):1454-67. Epub 2011 Nov 18., Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, Hartinger M, Windisch J, Casadevall N, London GM, Macdougall I., Sandoz Biopharmaceuticals, Hexal AG, Keltenring 1 + 3, 82041, Oberhaching, Germany, andreas.seidl@sandoz.com.

Overview of the paper

  • Two cases were noted of neutralizing antibodies to epoetin alfa in an investigational clinical study
  • During the investigation of this unwanted immunogenicity, a small number of individual syringes of two drug product batches were found to contain unusually high levels of aggregation at the end of the clinical trial
  • The scientists thus undertook an extensive analytical investigation to determine the root-cause of the increased aggregation in the affected batches
  • They found soluble tungsten in the syringes, most likely derived from the pins used to manufacture the syringes
    • Spiking of epoetin alfa with sodium polytungstate or an extract of tungsten pins used to manufacture the syringes induced the formation of aggregates:
      • the agrregated contained both dimers that appeared to be covalently linked by disulphide bonds as well as higher-order aggregates
    • Sodium polytungstate had also a strong denaturing effect on the protein
  • In conclustion, the authors propose that tungsten-mediated unfolding and aggregation of epoetin alfa in pre-filled syringes is a potential root cause for increased immunogenicity.
  • They also state that this finding may be more broadly applicable to this and other classes of therapeutic proteins

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22094831

BioQuality: what you need to know, when you need to know it. To subscribe: www.bioquality.biz

Brief Overview of ISPE/FDA 2012 Highlights

To start the conference, the first keynote speaker, CDER Director Dr. Janet Woodcock, gave an interesting talk “Vision for Quality in the 21st Century.” Topics she addressed in her presentation included:

  • What is the desired state, and have we achieved it?
  • The 2 faces of Quality in 2012
  • CDER’s progress
  • 21 CFR 211.100(a) and Quality by Design (QbD)
  • What has QbD delivered thus far?
  • Additional opportunities for QbD
  • FDA efforts in international collaboration
  • Status of progress towards the desired state
  • Industry Quality Systems
  • Root causes of failures
  • Quality Management of regulation

Other noteworthy talks during this excellent 2-day event included:

“Future Vision for the Office of Compliance,” by Ilisa Bernstein, FDA/CDER’s Acting Director of the Office of Compliance

“Culture of Quality,” by Mary Oates, Pfizer’s VP of Global Quality Operations

“International Regulatory Perspective,” by Gerald Heddell, Director of Inspection, Enforcement, and Standards for the UK’s Medicines and Healthcare Regulatory Agency (MHRA)

Still to come is a “meet the press” forum, and BioQuality will be there.

BioQuality subscribers will get summaries and analyses of these talks in upcoming issues. To subscribe: www.bioquality.biz


New EMA draft guidance on biopharma manufacturing in transgenic animals

New EMA draft guidance on biopharma manufacturing in transgenic animals

EMA, in the Executive Summary to this guidelines states “Transgenic animal technology has emerged as a complement to the longer-established range of prokaryotic, yeast and mammalian cell-based recombinant protein expression systems for the production of therapeutic proteins. In this document guidance is provided on the approaches that should be employed in order to achieve satisfactory quality for biological drug substances proposed to be produced using this technology.”

To see the draft guidance: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127961.pdf

Look for a comprehensive discussion of this new guidance in our June issue. To subscribe: www.bioquality.biz

BioQuality, what you need to know, when you need to know it.

Spotting, Tracking, and Predicting Inspection Trends

Spotting, Tracking, and Predicting Inspection Trends, Tom Pritchett, BioProcess International, Vol. 10, No. 6, June 2012, pp. 16–21

Link to free article: http://www.bioprocessintl.com/journal/2012/June/Spotting-Tracking-and-Predicting-Inspection-Trends-331145


Also see my earlier paper on a related subject: A 483 Primer, Tom Pritchett, BioProcess International, Vol. 9, No. 3, March 2011, pp. 12–16



And, if you’re into Cell Therapy or Biological Potency assays:

“Hard Cell,”  Tom Pritchett, Laureen Little, BioProcess International, Vol. 10, No. S3, March 2012, pp. 36–48



BioQuality, what you need to know, when you need to know it

Subscribe here: www.bioquality.biz

The latest papers on monoclonal antibody production

The 30 monoclonal antibodies authorized for marketing as human drugs represent, in terms of market share, the most important biotherapeutics. Two recent papers in Biotechnology Progress address GMP production of monoclonal antibodies. One deals with the important topic of process robustness, introducing a simulation tool to assess process robustness–current and future–in a mAb production facility. The second article presents a review of design and validation of downstream processing.

1) Decisional tool to assess current and future process robustness in an antibody purification facility, Stonier A, Simaria AS, Smith M, Farid SS, University College London, Department of Biochemical Engineering, Torrington Place, London, WC1E 7JE. UK; Lonza Biologics plc, MS&T, 228 Bath Road, Slough, SL1 4DX, UK, Biotechnol Prog. 2012 May 29. doi: 10.1002/btpr.1569 [Epub ahead of print]


  • Increases in cell culture titers in existing facilities have prompted efforts to identify strategies that alleviate purification bottlenecks whilst controlling costs
  • This paper describes the application of a database-driven dynamic simulation tool to identify optimal purification sizing strategies and visualise their robustness to future titer increases
  • The tool harnessed the benefits of MySQL to capture the process, business and risk features of multiple purification options and better manage the large datasets required for uncertainty analysis and optimization
  • The database was linked to a discrete-event simulation engine so as to model the dynamic features of biopharmaceutical manufacture and impact of resource constraints
  • For a given titer, the tool performed brute force optimisation so as to identify optimal purification sizing strategies that minimised the batch material cost whilst maintaining the schedule
  • The tool was applied to industrial case studies based on a platform monoclonal antibody purification process in a multisuite clinical scale manufacturing facility
    • The case studies assessed the robustness of optimal strategies to batch-to-batch titer variability and extended this to assess the long-term fit of the platform process as titers increase from 1 to 10 g/L, given a range of equipment sizes available to enable scale intensification efforts
  • Novel visualisation plots consisting of multiple Pareto frontiers with tie-lines connecting the position of optimal configurations over a given titer range were constructed
    • These enabled rapid identification of robust purification configurations given titer fluctuations, and the facility limit that the purification suites could handle in terms of the maximum titer and hence harvest load

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22641562

2) State of the art in downstream processing of monoclonal antibodies: Process trends in design and validation, Pa MG, Mm A, Centro de Biotecnología-FEMSA, Tecnológico de Monterrey at Monterrey, Av. Eugenio Garza Sada 2501, 64849 Monterrey, N.L., México, Biotechnol Prog. 2012 May 29. doi: 10.1002/btpr.1567. [Epub ahead of print]


  • Monoclonal antibodies are the most important family of biopharmaceutical compounds in terms of market share
  • At present, 30 monoclonal antibodies have been approved and are now commercialized for therapeutic purposes
  • Monoclonal antibodies are typically produced in widely-varying scale by mammalian cell culture in bioreactors
  • Regardless of scale, from laboratory to commercial settings, the recovery and purification of monoclonal antibodies presents important challenges
  • Depending on the scale, the particular product, and the type of production process (bioreactor operation, process time, complexity of the culture media, cell density, etc.), many possible downstream configurations are possible and have been used
  • The paper reviews each type of unit operation that forms a downstream train for monoclonal antibody production
  • The article also provides information regarding typical operation settings and critical variables for centrifugation, ultrafiltration, affinity chromatography, ion exchange chromatography, and viral removal operations
  • In addition, some important considerations required for the formulation of drugs based on monoclonal antibodies are discussed

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22641473

Subscribe to BioQuality and keep up with the latest regulatory and technical articles: www.bioquality.biz

Each week, BQ brings you a literature search which seeks papers on these and other important topics:

  • Adverse Event Monitoring and Reporting
  • Analytical Methods for Characterization and Control
  • Anti-drug Antibodies and Unwanted Immunogenicity
  • At the Cutting Edge
  • Basic Science Relevant to Biopharma and Biologics
  • Bioanalytical Methods and Issues
  • Biological Potency, Activity, and other Biological Assays
  • Biomarkers
  • Biosimilars, Follow-on Biologics, FOPPs, Biobetters, etc.
  • Business Articles and Reviews (this is actually a section, not a subsection–but it has no subsections under it and thus is listed here and in the QuickScan List)
  • Carbohydrate/Glycan/Oligosaccharide Characterization and Analysis
  • Cellular Therapies
  • Clinical Issues
  • Container/Closure Issues
  • Data Analysis and Statistics
  • Development Costs
  • Development Issues, Concerns, Strategies, etc.
  • Deviations, Handling and Reporting
  • Discovery Research
  • Distribution Issues
  • European Regulations and Regulatory Perspective
  • Excipient Analysis and Control
  • Formulation and Delivery
  • Gene Therapy
  • General Business Issues
  • GMP Compliance
  • Host Cell Proteins
  • Manufacturing and Production Issues
  • Method Qualification and Validation
  • Microbial Analysis and Control
  • Molecular and Personalized Medicine
  • Nucleic Acids
  • Particulate Analysis
  • Preclinical Issues
  • Process Monitoring, and Control, PAT
  • Process Development
  • Product Development, Pre-clinical and Clinical
  • Protein, Glycoprotein, Peptide, and Other Bio-molecule Structure/Function
  • Proteins, Glycoproteins, Peptides and Other Biomolecules: Characterization, Analysis, and Control
  • Quality by Design (QbD)
  • Raw Material Analysis and Control
  • Regulations, General Considerations
  • Regulatory Agencies
  • Regulatory Submissions, Review, Reporting, etc.
  • Reference Standard Qualification and Verification
  • Risk Analysis and Management
  • Safety and Efficacy Issues
  • Separation Science
  • Stability Issues
  • Surveillance and Pharmacovigilance
  • Vaccine Development, Testing, Control, Production, Delivery, etc.
  • Validation

Subscribe to BioQuality and keep up with the latest regulatory and technical articles: www.bioquality.biz



Propsed USP Chapter

Two new proposed USP chapters were presented and discussed at the recently-held AAPS National Biotechnology Conference. The proposed chapters are both numbered greater than 1000 and so are guidance, not mandatory, and will be of interest to biotechnology professionals.

Proposed USP <1106> was discussed in the previous post.

Proposed USP <1050.1>, meant to be a companion chapter to USP <1050>, addresses Design, Evaluation, and Characterization of Viral Clearance Procedures. According to moderator Robert Bell, Ph.D., from Drug and Biotechnology Development LLC, the purpose of the proposed chapter is to supplement <1050>, which is “long on philosophy, but short on details.” Topics discussed by him and co-moderators Jeri Ann Boose, Ph.D., from Lancaster Laboratories, and Ray Nims, Ph.D., from RMC Pharmaceutical Solutions, included:

  • A review of USP, the standard setting process, and expert committees
  • Background on existing Chapter <1050>
  • The scope of proposed <1050.1>
  • Experimental Design for viral clearance studies

To see the proposed chapters, go to the Pharmacopeial Forum website: www.usppf.com (access to Pharmacopeial Forum is free, after sign-up)

See this month’s BioQuality for a detailed discussion of this important new document. To subscribe: www.bioquality.biz

Propsed USP Chapter

USP <1106>, a proposed new USP Chapter on Immunogenicity Assays was presented and discussed yesterday at the 2012 National Biotechnology Conference sponsored by AAPS. The moderators were Maura Kibby, Ph.D. from the USP, Anthony Mire-Sluis, Ph.D. from Amgen, and Meena Subramanyam, Ph.D., from Biogen Idec. Topics discussed included:

  • History and Scope of <1106>
  • Why <1106> is needed
  • An Outline of the propsed Chapter
  • Design of cut points for both screening and confirmation assays
  • Assay sensitivity in:
    • the absence of drug
    • the presence of drug
  • Current status and next steps

To see the proposed chapter: www.usppf.com (access to Pharmacopeial Forum is free, after sign-up)

See this month’s BioQuality for a detailed discussion of this important new document. To subscribe: www.bioquality.biz

EMA Pharmacovigilance Training

The European Medicines Agency has launched an e-learning course for marketing authorisation holders to support compliance with Article 57(2) on the submission of information on medicines, one of the key measures of the new pharmacovigilance legislation.

The course is comprised of six modules which cover:

  • an introduction to the Eudravigilance system;
  • the regulatory background;
  • the architecture of the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD);
  • submission of the eXtended EudraVigilance Product Report Message (XEVPRM) with practical examples, and;
  • the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) data entry tool also known as EVWEB.

The modules are free to access and can be streamed live now or will be available for downloading (download will be available early next week). Part of the course is a knowledge evaluation test. A notification of successful completion of this test will be required for one user before the electronic submission process can be initiated by a MAH as per Article 57(2) of Regulation (EU) No 1235/2010.

EMA recommends that at least one user from each marketing authorisation holder should be trained to understand how to submit medicinal product data to the Agency and to ensure quality of medicinal product data submitted to the eXtended EudraVigilance Medicinal Product Dictionary (XEVMPD).

To see the training programme: http://eudravigilance.ema.europa.eu/human/training7.asp

BioQuality, what you need to know when you need to know it: www.bioquality.biz

Accorda Therapeutics Warning Letter

Pharma/biopharma manufacturer/developer Accorda Therapeutics received a Warning Letter on May 9 after an inspection between August 15, 2011 and September 9, 2011 revealed inadequacies in the firm’s adverse event handling procedures. Major issues in the WL are:

  • Failure to submit all adverse drug experiences (ADEs) that are both serious and unexpected to FDA within 15 calendar days of initial receipt of the information as required by 21 CFR 314.80(c)(1)(i)
  • Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences (ADEs) from all sources as required by 21 CFR 314.80(b)
  • Failure to maintain records of all adverse drug experiences known to you, including raw data and any correspondence relating to adverse drug experiences, for a period of 10 years as required by 21 CFR 314.80(i)
  • Failure to report each adverse drug experience not reported under 21 CFR 314.80(c)(1)(i) at quarterly intervals as required by 21 CFR 314.80(c)(2)(i).

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