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Uncategorized | BioQuality.biz - Part 3

Recent Warning Letters reveal FDA foreign enforcement priorities

Warning Letters to foreign bio/pharma manufacturing firms reveal some common focus areas, including:

  • Separation of API production areas
  • Review of documents and procedures by QA
  • Prevention of microbial contamination
  • Several more areas; these will be published and analyzed in this month’s BioQuality

BioQuality subscribers will receive a detailed analysis of these WLs in the next weekly update edition; to subscribe, go to: www.bioquality.biz

Recent Media Fill Process Simulation 483s

Media fill process simulations are a crucial part of demonstrating that an aseptic process remains in a state of control. However, FDA and other regulatory agencies are very demanding when it comes to compliant execution of these studies. Review the items below from recent inspections to make sure you are not making the same mistakes.


Firm’s media fills are deficient and do not follow the firm’s SOPs for media fills:

  • Not all the manufacturing operators perform the SOP-specified interventions as required by the procedure
  • Media filled vials in the area of the interventions are not incubated, and:
  • Discarding these vials precludes the Quality Init from adequately assessing and assuring that the manual interventions do not create or provide:
    • adverse conditions that can result in having microbial and /or non-viable contamination
  • The firm does not have a scientific rationale to support discarding and not incubating the vials from the intervention zone
  • The firm’s media fill SOP does not permit or discuss discarding of intervention zone vials
  • Multiple interventions occur simultaneously during routine aseptic filling, but multiple simultaneous interventions are not included in the media fill process simulations

Firm’s media fill process simulations are insufficient to establish that the aseptic process is in control, for example:

  • Firm failed to  establish appropriate criteria for reconciliation of filled vials (total units evaluated/incubated as compared to:
    • the total number of units filled) resulting in inconsistent and inaccurate media fill results
  • For many studies, the number of units filled did not match the number being evaluated/incubated:
    • the number of units evaluated/incubated in some media fill runs was smaller than what had been filled
  • In other media fill runs, the number of units evaluated/incubated was greater than what had been filled. Moreover, firm lacked a justification for these discrepancies

Procedure designed to prevent microbial contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process, specifically:

  • The firm’s aseptic filling process simulation runs (media fills) designed to validate the aseptic filling of drug product are deficient in that: Modifications to vial filler and restricted access barrier were made after qualification and media fill runs were performed, these modifications were approved without requalification and subsequent successful media fills

Subscribe to BioQuality and keep up with inspection results and much more: www.bioquality.biz

New Review of Protein Particulate Detection Issues

Pfizer scientist TK Das has written and published a useful review for those developing protein drugs:

AAPS PharmSciTech. 2012 May 8. [Epub ahead of print], Protein Particulate Detection Issues in Biotherapeutics Development-Current Status, Das TK, Pfizer Biotherapeutics Pharmaceutical Sciences, 700 Chesterfield Parkway West, Chesterfield, Missouri, 63017, USA, tapan.k.das@pfizer.com.

This article provides an overview of emerging detection technologies that provide complementary characterization data encompassing a wider size range of particulates. It also discusses their advantages and limitations in the context of applications in biotherapeutics development. Here are some highlights from the paper:

  • Protein particulates can form in a wide range of sizes and shapes
  • Formation of aggregates and particulates in biopharmaceutical formulation continues to be one of the major quality concerns in biotherapeutics development
  • The presence of large quantities of aggregates is believed to be one of the causes of unwanted immunogenic responses
  • Comprehensive characterization of particulates in biologics formulation continues to be challenging
  • However, recent years have seen a significant increase in the development of newer technologies for more comprehensive characterization of particulates
  • It is well recognized that research on particulates in the submicron (<1 μm) and low-micron (1-10 μm) ranges may provide important clues to understand the mechanism of particulate formation

To see the abstract and information on obtaining this paper: http://www.ncbi.nlm.nih.gov/pubmed/22566174

Each week BioQuality subscribers receive a comprehensive listing of important new regulatory and technical papers. Subscribe today @ www.bioquality.biz




FDA Update. FDA/CDER/Office of Compliance Acting Director Ilisa B.G. Bernstein, PharmD, JD, and Connie T. Jung, RPh, PhD, Acting Associate Director for Policy and Communications Office of Drug Security, Integrity, and Recalls FDA/CDER/Office of Compliance presented, at a recent conference, an update on select FDA activities during the past year.

Here are some salient points from the presentation:

  • New molecular entity (NME) approvals by CDER, after a dip down to 20 during fiscal year (FY) 2010, returned, at 30 approvals during FY 2011, to near the FY 2009 level of 31 approvals
  • Regarding Risk Evaluation and Mitigation Strategies (REMS), the agency released Final Medication Guide Guidance for Industry in November 2011 (http://www.fda.gov/Drugs/DrugSafety/UCM085729)
  • Recall events for FY 2012, first quarter (99 events), were keeping pace with FY 2011 levels (419 events for the whole year), but the number of recalled products topped 1,100 (1146 products) in the first quarter, on pace to exceed the entire FY 2011 number (1616 products)
  • The top reasons for major recalls during FY 2010, 2011 and 2012 up to 7-March were:
    • subcribers received this information in our first weekly May issue
    • subscribe to BioQuality and get the whole picture: www.bioquality.biz

Recent FDA Warning Letters to Foreign Firms

In the past 3 months, FDA has issue 5 Warning Letters to foreign firms possibly of interest to BioQuality News readers. The companies are: API manufacturer Nobilus Ent, Poland; Sterile products manufacturers Smithkline Beecham, UK, Gulf Pharmaceuticals, UAE, and Wintac, India; Contract Testing Lab UNAM, Mexico.

BioQuality subscribers will receive summaries of these WLs in the next weekly edition. Subscribe here: www.bioquality.biz

Recent Blog Buzz

“Policy changes and enforcement strategies implemented by the FDA have led to an increase in the number of inspections of both Contract Manufacturing Operations (CMOs) and in-house sterile manufacturers — especially injectables,” Barry A Friedman, PhD LLC writes, in an article titled CURRENT CONTRACT MANUFACTURING OPERATION (CMO) REGULATORY ISSUES, on his FDA Warning Letters and USP Updates blog (http://barryafriedmanphdllc.wordpress.com/). He goes on to say that “Contract Manufacturing Operations, in particular, must now have strategies to ensure GMP compliance at their facilities involved in ‘arm’s length’ activities with innovator and generic firms and be prepared for more frequent and thorough audits.” To see the whole article visit the blog, or point your browser to: http://barryafriedmanphdllc.wordpress.com/2012/03/15/current-contract-manufacturing-operation-cmo-regulatory-issues-31512/


And, talk about the cost of noncompliance, now if you fail an FDA inspection, you really pay. OK, OK, the discussion below  is about food, but I think it may also serve as a heads up for drug and biologics firms–FDA has a habit of rolling out new programs in either food or devices and then broadening the application to other regulated products:

Attorney Ricardo Carvajal, writing for the FDA Law Blog (http://www.fdalawblog.net/fda_law_blog_hyman_phelps/), shows how ” Warning letters issued by FDA since late February provide an indication of the types of violations that could trigger reinspection fees under the authority provided by the Food Safety Modernization Act (“FSMA”),” which granted FDA the authority to collect fees for a reinspection after a previous inspection that was classified as Official Action Indicated (OIA).  An inspection is classified as OAI if significant objectionable conditions or practices were found and regulatory action is warranted to address non-compliance.

The attorney notes that ” Warning letters to firms subject to reinspection fees now include the following notice:
Section 743 of the Act (21 U.S.C. § 379j-31) authorizes FDA to assess and collect fees to cover FDA’s costs for certain activities, including costs related to re-inspection. A re-inspection is one or more inspections conducted subsequent to an inspection that identified non-compliance materially related to a food safety requirement of the Act, specifically to determine whether compliance has been achieved. Re-inspection-related costs means all expenses, including administrative expenses, incurred in connection with FDA’s arranging, conducting, and evaluating the results of the re-inspection and assessing and collecting the re-inspection fees, 21 U.S.C. § 379j-31(a)(2)(B). For a domestic facility, FDA will assess and collect fees for re-inspection-related costs from the responsible party for the domestic facility. The inspection noted in this letter identified non-compliance materially related to a food safety requirement of the Act. Accordingly, FDA may assess fees to cover any costs related to re-inspection.”

He further advises that “Given the broad range of circumstances under which reinspection fees could be assessed, firms would be well advised to manage their inspections and follow-up corrective actions accordingly.”

Who wants to bet that in a fiscal year or so, re-inspection fees will be coming to our world? To see the article: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/04/warning-letters-begin-addressing-fsma-reinspection-fees.html


The requirements of EU GMP Annex 11 “Computerised Systems,” went into force 30-June, 2011. To assist with implementation……….. Subscribe to BioQuality and get the whole buzz: www.bioquality.biz

A sampling of important new biopharmaceutical papers from the literature

Each week BioQuality staff search the scientific literature for papers you should read, or at least know about. Following is a sample of recent discoveries.

Topic: Biosimilars

Multivariate statistics for the differentiation of erythropoietin preparations based on intact glycoforms determined by CE-MS, Taichrib A, Pioch M, Neusüß C., Anal Bioanal Chem. 2012 May;403(3):797-805. Epub 2012 Mar 20. To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22430131


Topic: Cellular Therapies

Human mesenchymal stem cell culture: rapid and efficient isolation and expansion in a defined serum-free medium, Jung S, Sen A, Rosenberg L, Behie LA., J Tissue Eng Regen Med. 2012 May;6(5):391-403. doi: 10.1002/term.441. Epub 2011 Jul 11. To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/21744510

Clinical applications and biosafety of human adult mesenchymal stem cells, Mariani E, Facchini A., Curr Pharm Des. 2012 May 1;18(13):1821-45. To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22352750


Topic: Manufacturing and Production

Effects of high passage cultivation on CHO cells: a global analysis, Beckmann TF, Krämer O, Klausing S, Heinrich C, Thüte T, Büntemeyer H, Hoffrogge R, Noll T., Appl Microbiol Biotechnol. 2012 May;94(3):659-71. Epub 2012 Feb 14.
To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22331235

Topic: Characterization and Control of Biopharmaceuticals and Biologics

Residual metals cause variability in methionine oxidation measurements in protein pharmaceuticals using LC-UV/MS peptide mapping, Zang L, Carlage T, Murphy D, Frenkel R, Bryngelson P, Madsen M, Lyubarskaya Y., J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:71-6. Epub 2012 Mar 20. To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22483985


Topic: The Business of Biopharmaceuticals and Biologics

The biopharmaceutical industry in China: history and future perspectives, Gao K, Wang J., Front Med. 2012 Apr 28. [Epub ahead of print]
To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22544299

Every week, BioQuality Subcribers receive references like these to crucial new papers appearing in the literature. Do you really have the time to do your own searches? Can you afford to miss these papers and the knowledge they contain? Subscribe to BQ at www.bioquality.biz,  and rest assured that you will know about any new papers about the topics you care about, including:

Adverse Event Monitoring and Reporting

Analytical Methods for Characterization and Control

At the Cutting Edge

Basic Science Relevant to Biopharma and Biologics

Bioanalytical Methods and Issues

Biological Potency and other Biological Assays


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

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 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

Unwanted Immunogenicity

Vaccine Testing, Control, Production, Delivery, and other Issues



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






New Media Fill Guidance from FDA

FDA has released a Media Fill Guidance Document. The document is aimed at producers of positron emission tomography (PET) drugs, who requested guidance on this subject during meetings with FDA to discuss new regulations going into effect mid-June of this year. However, this guidance, which is in question and answer form, gives advice on media fills that should be of benefit to all involved in aseptic processing.

The media fill questions answered by FDA in the guidance document include:

  • What is a media fill?
  • What is the media fill designed to evaluate?
  • What are the steps involved in a media fill?
  • How do I choose the growth medium?
  • How often should a media fill be performed?
  • A media vendor is typically qualified by testing three batches of medium, How do I do that?
  • What is growth promotion testing?
  • What is the difference between growth promotion test and a positive control?
  • When do I use a positive control?

To see the Guidance:


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483s from recent inspection of Tissue Establishment ItelliCell Biosicences

Human Tissue Establishment ItelliCell Biosciences received a  6-page Form 483 during an inspection that took placed over 4 days  between November 8 and December 12 or last year. Following are some highlights of the 13 deficiency observations, all rather serious, noted by FDA:

  • Buildings used in the manufacturing and processing of drug product are not maintained in a good state of repair
  • Records are not kept for the maintenance, cleaning, sanitizing, and inspection of equipment
  • The control systems necessary to prevent contamination or mix-ups are deficient
  • There is no quality control unit
  • Procedures describing the handling of all written and oral complaints regarding a drug product are not established, written, and followed
  • The distinctive code for each lot of components and drug product containers is not used in recording the disposition ofeach lot
  • Written procedures are lacking which describe in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval, and rejection of components
  • Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, in-process materials, and drug products conform to appropriate standards of identity, strength, quality and purity
  • Deviations from written production and process control procedures are not justified
  • Established test procedures and laboratory control mechanisms are not followed and documented at the time of performance
  • There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess
  • Each batch of drug product required to be free of objectionable microorganisms is not tested through appropriate laboratory testing
  • Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and written

“There is no quality control unit?” Yikes! You can see the entire form 483 to get the specifics here: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/UCM298740.pdf


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


BioBetters and Biosimilars

At a recent IBC conference titled “BioBetters and BioSimilars: Technologies and Development Strategy”, BioBetter presentations far out-numbered BioSimilar presentations. Is there really more interest in BioBetters? And, by the way, just what is a BioBetter?

According to speaker Bill Strohl, PhD. Vice President Biologics Research from Janssen, a BioBetter is “..a biologic molecule based on the innovator molecule but with improvements intended to increase efficacy, potency, marketability, safety, or patient compliance.”

This is in contrast to next generation products which are based on the same validated target as an innovator biologic but with novel structures (such as the VH/VL chains) and to a BioSimilar, which by definition cannot differ from the comparator product too much. (How much change is too much was a topic raised frequently by meeting attendees.)

Why all the interest in BioBetters?

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