Who is Responsible for Ensuring GMP Compliance?

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A recent case from Denmark demonstrated that senior management really is responsible for GMP compliance. The Danish Medicines Agency (DKMA) has now taken an action that reinforces  senior management responsibility in a very significant way: they demanded the replacement of the CEO!

It’s important that senior management understand their critical role in implementing a compliant Pharmaceutical Quality System (PQS) and in creating a good quality culture.

Share this with your senior management.

EMA Guideline on the Chemistry of Active Substances

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Active Substance

Are you preparing submissions to the EMA for marketing authorization this year?  This guideline goes into effect in July 2017 and describes the type of information required for the manufacture and control of active substances used in medicinal products for EMA marketing authorization. It replaces the “Note for guidance on chemistry of new active” (CPMP/QWP/130/96, Rev 1) and “Chemistry of active substances” (3AQ5a) and covers new and existing active substances in one guideline. 

Read more here

European Medicines Agency (EMA) Mutual Recognition Agreement (MRA)

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The EMA and FDA have agreed to recognize each other’s GMP inspections.  This Mutual Recognition Agreement goes into effect on November 1, 2017 to allow each other to:

  • rely on each other’s GMP inspections;
  • waive any requirements for batch testing of products on entry into their territories, after a transition phase;
  • share information on inspection outcomes and quality defects.

    This means that FDA inspections in the EU or EU inspections in the USA should be only performed in exceptional cases.

Read more here.

Updated GMP Inspection Process

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The FDA’s newly formed Office of Pharmaceutical Quality (OPQ) will update its GMP inspections process to add risk-based factors to give sites with higher risk more attention and reward sites that exceed basic compliance.

This New Inspection Protocol Project (NIPP) changes GMP inspections by standardizing data gathering during inspections, using a question-answer based reports with a semi-quantitative scoring to allow for comparisons within and between sites, and a common inspection report structure.

The NIPP program is expected to start in 2017 as a pilot program to collect feedback and experience from the inspectors before it is formally implemented. As FDA inspections become more transparent and semi-quantitative, it is bound to be mutually beneficial to both FDA and the industry. The program was one of the 5 areas of priority for OPQ.


Proposed New USP General Chapter: The Analytical Procedure Lifecycle

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ABSTRACT (from the document): An analytical procedure must be demonstrated to be fit for its intended purpose. It is useful to consider the entire lifecycle of an analytical procedure, i.e., its design and development, qualification, and continued verification. The current concepts of validation, verification, and transfer of procedures address portions of the lifecycle but do not consider it holistically. The purpose of this proposed new chapter is to more fully address the entire procedure lifecycle and define concepts that may be useful. This approach is consistent with the concept of quality by design (QbD) as described in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11. The lifecycle approach can potentially be applied to all procedures, although the level of effort should be consistent with the complexity and criticality of the procedure.

FDA Guidance for Pharmaceutical CMO Quality Agreements

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Quality agreements are critical to ensure you and your contract manufacturer define each other’s roles and responsibilities with respect to quality. On November 22, 2016, the FDA released the finalized guidelines that specify what should go into quality agreements between pharmaceutical companies and outsourced contract manufacturers.

This guidance applies to commercial manufacturing for human drugs, veterinary drugs, certain combination products, biological and biotechnology products, finished products, APIs, drug substances, in-process materials, and drug constituents of combination drug/device products.

It does not apply to Type A medicated articles and medicated feed, medical devices, dietary supplements, or human cells, tissues, or cellular or tissue-based products regulated solely under section 361 of the Public Health Service Act and 21 CFR part 1271.

Download the guidance here.

Quality Metrics – New Guidance from FDA

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Quality metrics are used throughout our industry to drive continuous improvement efforts in manufacturing. Collecting the right quality metrics is critical to ensure compliance. Quality metrics can also help the FDA in developing compliance and inspection policies and procedures by allowing the FDA to:

  • Use a risk-based inspection scheduling of drug manufacturers
  • Improve ability to predict and possibly mitigate future drug shortages
  • Encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for manufacturing.

The revised draft guidance includes an explanation of how the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) intend to utilize submitted data and quality metrics to help ensure that their policies and practices continue to support continuous improvement and innovation.

FDA is initiating a voluntary reporting phase of the FDA quality metrics reporting program where they expect to learn more about a limited set of quality metrics, associated analytics, and improve the FDA quality metrics reporting program.

During the voluntary phase of the reporting program, FDA will accept voluntary submissions of data from drug manufacturing firms involved in the manufacture, preparation, propagation, compounding, or processing of finished dosage forms (FDF) or active pharmaceutical ingredients (API) used in the manufacture of “covered drug products.”

For more information and to download the guidance, click here.

Storage and Transport of Investigational Drug Products (IDP)

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Does your company handle investigational drug products (IDP) the same as your commercial products? If so, you may want to consider the proposed new USP chapter on storage and transport of IDP as an addition to the Good Storage and Distribution Practices for Drug Products chapters [1079]. This new subchapter should focus on investigational drug products (IDPs; investigational medicinal products in Europe, IMPs). Transport of small quantities of product to multiple sites, minimal stability data, temperature excursions of single containers along with different distribution requirements in various countries make this a challenge for most companies. To address these challenges, the new chapter proposes the following requirements:

  • Storage in a safe and secured area at labelled storage conditions
  • Segregation for IDPs not dispensed yet and for IDPs awaiting return to sponsor or contractor
  • Site qualification audits need to be performed
  • Anticipation and tracking of expiry or re-test extensions (according to different local regulatory requirements)
  • Packaging qualifications should be the same as for commercially available drug products
  • Consideration of important distribution risk factors (e.g. distance, time, temperature, handoffs, packaging)
  • Confirmation that proper steps are taken to ensure IDP supply chain integrity (including checklists for patients)
  • Unblinded IDPs should be quarantined
  • Comparators should be shipped and stored according their (new) IDP labeling

This new chapter also gives a detailed example for calculating a rating of shipment risk to help identify probability and impact of errors in the supply chain.

Read more on the USP Pharmacopeial Forum.

FDA Requires Use of eCTD Format and Standardized Study Data in Future Regulatory Submissions

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FDA will now require that certain regulatory submissions conform to the electronic Common Technical Document (eCTD) format. In addition, study data will have to be submitted in standardized format for certain studies.  The eCTD has been the standard format for submitting applications, amendments, supplements, and reports to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) since 2008 and makes it easier for FDA to review data, approve new drugs, and monitor drugs after they go on the market. It also simplifies the process for submitters, because the CTD format is used by drug regulatory agencies in many countries.

Starting on May 5, 2017, eCTD will be required for applications submitted to CDER and CBER for the following:

  • New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), Biologics License Applications (BLAs), and all subsequent submissions to these types of applications, including amendments, supplements, and reports, even if the original submission was filed before the requirements went into effect.
  • Master files, such as Drug Master Files (DMFs), which are considered to be submissions to an IND, NDA, ANDA, or BLA.
  • Combination products (if CDER or CBER is designated as the lead center).

Download the guidance here.

For a complete listing of all documents and supportive files needed in order to submitelectronically, refer to the eCTD Web page at



Use of International Standard ISO 10993-1, “Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing Within a Risk Management Process”

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Does your medical device come into direct or indirect contact with the human body?   If so, the FDA has released a guidance document on the Use of International Standard ISO 10993-1. This guidance will help you determine the potential for an unacceptable adverse biological response resulting from contact of the component materials of the device with the body.  The scope is limited to the biological evaluation of sterile and non-sterile medical devices that come into direct or indirect contact with the human body.  It specifically covers the use of ISO 10993-1 but also is relevant to other biocompatibility standards (e.g., other parts of the ISO 10993 series of standards, ASTM, ICH, OECD, USP).  Topics covered in this guidance are:

  • Use of risk assessments for biocompatibility evaluations for a proposed medical device
  • Use of ISO 10993-1 and the FDA-modified matrix to determine the relevant biocompatibility endpoints for an evaluation
  • General biocompatibility testing considerations, including test article preparation;
  • Specific considerations for the following testing: cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and degradation assessments
  • Chemical assessment recommendations
  • Considerations for labeling devices as “-free.”

It also contains valuable resources in the appendices such as: Device Master Files for Biocompatibility Evaluations, Summary Biocompatibility Documentation, Biocompatibility Evaluation Flow Chart, Content of a Biocompatibility Test Report and Component and Device Documentation Examples.

Download the guidance here.