EU Council adopts the Falsified Medicines Directive

Recently, the EU Council adopted the Falsified Medicines Directive. The directive reflects substantial changes regarding GMP and GDP (good distribution practices) for both finished product, API, and excipients. The objective of the revised directive is to prevent the entry into the legal supply chain of drug product any API or excipient that is falsified relative to its identity, history or source. Although this is an EU directive, we anticipate that the US will follow suit within the next year or so. There has been significant communication of late, from FDA, about protection of the supply chain. The publication by the Council of the European Union summarizes the expectations of this new directive.

Highlights of the changes:

  • Imported APIs from non-EU origin must be accompanied by a written confirmation of compliance unless: the exporting country is on the list of equivalent countries; and, for exceptional reasons of a medicine’s availability and when the EU GMP certificate is not older than 3 years and the European Commission is informed.
  • Manufacturers, importers, distributors and brokers of APIs must register their activities with the Competent Authority where the operator is established. Annual notification of changes is mandatory. Changes impacting quality or safety have to be notified immediately.
  • Harmonization of safety features for APIs, excipients and medicinal products to allow verification of the authenticity and identification of individual packs, and provide evidence of tampering.
  • The final dosage form manufacturer must perform a formal risk assessment to establish which GMP requirements should apply to the excipients used for drug product manufacture. The drug manufacturer should consider the source of the excipients, the intended use and previous quality incidents have to be taken into account.

This document implies that a more rigorous audit program should be considered to ensure that good manufacturing practices are complied with for all API and excipient manufacturers, distributors, and repackagers. This is in line with what we are seeing on the US front from FDA as well.

New Guideline on Bioanalytical Method Validation

The Committee for Medicinal Products for Human Use (CHMP) adopted the Guideline on bioanalytical method validation. This document defines the key elements to consider for validation of bioanalytical methods. the document was released in June 2011 and becomes effective in Feb. 2012.

Bioanalytical methods are used to support animal tox and clinical studies. The measurement of drug concentrations in biological matrices like blood, urine, saliva, etc., is an important part of drug development and supports regulatory filings. Therefore, characterization and validation of these methods is important.

Read the EMEA memo here.

Draft Guidance: Applying Human Factors and Usability Engineering

FDA has published the Draft Guidance, “Applying Human Factors and Usability Engineering to Optimize Medical Device Design” (June 2011). When final, this document will replace the FDA Guidance “Medical Devices Use-Safety: Incorporating Human Factors Engineering into Risk Management” (published on 18 July 2000).

The guidance suggests what to consider and how to perform appropriate human factors testing on medical devices in order to reduce use error, injury, and prevent recall. The FDA believes that these recommendations will help control current risks and reduce future risks associated with device use.

Read and download the draft guidance here.

EU Commission publishes new draft guideline on Good Distribution Practice

EU Commission publishes new draft guideline on Good Distribution Practice for review by December 31, 2011.

The EU has published for comment a much more stringent set of guidelines for Good Distribution Practices. These guidelines reflect current EU and FDA thinking on security of the global supply chain, more involved vendor management, computerized systems and qualification/validation, documentation, risk management, and transportation. The guidelines are the outcome of the requirements of the new EU Directive on Falsified Medicines.

Read the guidelines here.

Draft Guidance for Industry and FDA Staff Processing/Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling

When final, this guidance will supersede Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: FDA Reviewer Guidance. This draft guidance document updates and clarifies the recommended content of, and review procedures for, premarket notification submissions [510(k)], premarket approval (PMA) applications, humanitarian device exemption (HDE) applications, and investigational device exemptions applications (IDE), concerning the labeling instructions for reprocessing reusable medical devices. In addition, this draft document provides more detail about FDA’s recommendations for the validation of processes intended to support reprocessing.

This guidance provides recommendations regarding reuse instructions in labeling for reusable medical devices and the validation of the recommended reprocessing process in the instructions. The recommendations are applicable to the three device reprocessing situations below.

  1. Reusable medical devices initially supplied as sterile to the end user and requiring the end user to process the device after initial use (i.e., cleaning and disinfection or sterilization) prior to the subsequent patient use.
  2. Reusable medical devices initially supplied as non-sterile to the end user, and requiring the end user to disinfect or sterilize the initial packaged device and to subsequently reprocess the device after initial use (i.e., cleaning and disinfection or sterilization).
  3. Single use medical devices initially supplied as non-sterile to the end user, and requiring the end user to sterilize the device prior to its use.

Read and download the draft guidance here.

510(k) Device Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device

In late July 2011, The FDA published a draft document of “510 (k) Device Modifications: Deciding When to Submit a 510 (k) for a Change to an Existing Device”. This draft updates FDA’s current position on when a modification to an existing medical device would trigger the requirement to submit a new 510(k) premarket notification.. When final, this guidance will supersede the 1997 “Deciding When to Submit a 510 (k) for a Change to an Existing 510(k)” guidance.The guidance has been updated to address issues associated with software and other rapidly changing technologies, and to provide greater clarity about changes that do not trigger the need for a new premarket submission.The types of modifications addressed include manufacturing process changes, labeling changes, technology or performance specification changes, and material changes.

Access the full draft guidance here.

Q11: Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities) Draft No. Step 2 Document

This guideline describes approaches to developing process and drug substance 66 understanding and also provides guidance on what information should be provided in CTD sections 3.2.S.2.2 – 3.2.S.2.6. It provides further clarification on the principles 68 and concepts described in ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9) and Pharmaceutical Quality Systems (Q10) as they pertain to the development and manufacture of drug substance. A company can choose to follow different approaches in developing a drug substance.

For the purpose of this guideline, the terms “traditional” and “enhanced” are used to differentiate two possible approaches. In a traditional approach, set points and operating ranges for process parameters are defined and the drug substance control strategy is typically based on demonstration of process reproducibility and testing to meet established acceptance criteria. In an enhanced approach, risk management and more extensive scientific knowledge are used to select process parameters and unit operations that impact critical quality attributes (CQAs) for evaluation in further studies to establish any design space(s) and control strategies applicable over the lifecycle of the drug substance. As discussed in ICH Q8 for drug product, a greater understanding of the drug substance and its manufacturing process can create the basis for more flexible regulatory approaches. The degree of regulatory flexibility is generally predicated on the level of relevant scientific knowledge provided in the application for marketing authorization. Traditional and enhanced approaches are not mutually exclusive. A company can use either a traditional approach or an enhanced approach to drug substance development, or a combination of both.

Read and download the guidelines here.

FDA presents a Q&A on the current TBA/Wooden Pallet issue that has resulted in several drug recalls

“The source of TBA-contaminated drug products appears to have been 2,4,6-tribromophenol (TBP), a chemical used as a wood preservative. Certain fungi are able to survive in TBP-treated wood by converting TBP to its anisole analog, TBA[1]. In the recent contamination incident, an investigation found that TBP-treated wood was used to manufacture pallets that were then used to ship and store drug packaging material. Currently, the use of halogenated phenolic compounds to preserve wood appears to be very rare as this practice is either discouraged or prohibited in many regions of the world, including the US. However, TBP treatment of wood continues in some regions that supply wood to the US and other countries.”

Read more here:

Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance Buildings and FacilitiesQuestions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance Buildings and Facilities

New MWA Products: Medical Device Checklists

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Checklist 1: 21 CFR 820 The Quality System Regulation and 13485:2003 Medical devices – Quality management systems – Requirements for regulatory purposes

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Checklist 3: 21 CFR 803 and 806 – Medical Device Reporting / Recall

Checklist 4: ISO 14971:2009 Medical devices – Application of risk management to medical devices

Checklist 5: 21 CFR 820.30 Design control + EN 60601-1 Third Edition

Checklist 6: 510(k) Traditional or Abbreviated Readiness