FDA Issues Draft Guidance on Post Approval Drug Safety Issues

FDA is seeking public comment on this guidance that details a system for handling postmarket drug safety issues, including drug quality and serious adverse events. CDER will use hazard assessment criteria and will then apply certain modulating factors to classify a newly identified safety issue. CDER staff will first apply the criteria used to estimate the hazard to yield a preliminary classification of either priority or standard.

Priority issues may then be classified as emergencies, if they have involved fatalities, have the potential to affect a very large number of patients, and if lives can be saved or if serious harm can be prevented by prompt action. Emergency issues will be immediately elevated to the attention of senior management. All tracked safety issues (TSIs) not classified as priority or emergency following this approach will be considered standard.

The hazard is then judged against three factors:

(1) the relative seriousness of the issue; (2) the estimated size of the population exposed to the risk of the drug; and (3) the suspected frequency of harm to patients exposed to the drug. The combination of factors 2 and 3 provides an estimate of population risk; the combination of factors 1 and 3 provides an estimate of personal risk to the patient.

Here is the guidance in pdf form.

All you want to know about HVAC operating parameters from World Health Organizati‚Äčon (WHO)

WHO Issues Revised Annex 5: Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms, July 2011.

This modified annex is meant to supplement the GMPs and address basis non-sterile dosage form HVAC considerations. The primary areas covered in this annex are the roles that the HVAC system plays in product protection, personnel protection, and environmental protection. The annex does reference ISO 14644 for qualification and validation for particle count, air pressure differences, airflow volume, airflow velocity, filter leakage tests, containment leakage, recovery and airflow visualization.

This is a useful guideline for consideration when addressing facility redesign, new facility design, or when assessing a CMO’s compliance with HVAC operations and maintenance.

Read the guidance here.

FDA Issues Guideline on Anti-Counterfeiting Medicines: October 2011

FDA issued this document to provide guidance to pharmaceutical manufacturers who want to use physical-chemical identifiers (PCIDs) in their solid oral dosage forms to prevent/ reduce the potential for counterfeiting. The use of PCIDs is to unequivocally identify and authenticate a drug product or a dosage form (SOFD). Although the proclaimed statistics related to counterfeit drugs by WHO appear to be unsubstantiated, it appears that the industry is experiencing an increase in the number of counterfeit drugs that are entering into our supply chain. Therefore, ensuring the integrity of the supply chain is paramount to ensuring that patients get the proper drug in the proper dosage form, tested to conformance with stringent specifications.

This guidance provides recommendations to pharmaceutical manufacturers on (1) design considerations for incorporating PCIDS into SODFs, (2) supporting documentation to be submitted in new drug applications (NDAs) and abbreviated new drug applications (ANDAs) to address the proposed incorporation of PCIDs in SODFs, (3) supporting documentation to be submitted in post-approval submissions to report or request approval to incorporate PCIDs into SODFs, and (4) procedures for reporting or requesting approval to incorporate PCIDs into SODFs as a post-approval change.

Read the guidance here.

How does the FDA interpret the regulations (21 CFR Part 211) regarding the establishment of expiry dating for chemicals, reagents, solutions, and solvents?

Finally, we get to see in writing what are the expectations regarding lab reagents, prepared solutions, and reference standards.

This explanation is taken verbatim from the FDA Q&A.

Laboratory “reagents, and standard solutions,” as referenced in the CGMP regulations at 211.194, includes laboratory chemicals such as solvents (including mobile phases), dry chemicals (salts, primary standards, etc.), and solutions (buffers, acids/bases, quantitative analytical preparations, etc.), whether purchased or prepared in-house. Laboratory reagents and solutions are used in analytical tests of components, in-process materials, and finished products.

If the purchased laboratory reagent or solution includes a manufacturer’s suggested “use by” or expiry date, that date should be followed. For purchased laboratory reagents and solutions without a “use by” or expiry date, FDA would expect that an assessment be conducted (literature review may be acceptable) of that specific chemical’s or chemical family’s stability and that an appropriate “use by” or expiry date be determined. For in-house prepared solutions, such as mobile phases or other non-quantitative solutions, FDA would expect that an assessment be conducted (again, literature review may be acceptable) to determine an appropriate expiry period. However, for in-house prepared solutions used for quantitative analysis, such as sample or standard solutions used in assay or impurity testing or titration solutions, FDA requires that formal stability studies be conducted to determine an appropriate expiry. As mentioned in Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, the stability of analytical solutions is a typical method variation that should be evaluated during robustness testing during method validation. Method validation is a CGMP requirement at 211.160(b).

The determined “use by” or expiry dates should be documented within a procedure and followed. Procedures for any in-house prepared laboratory solution should include the determined stability timeframe, and should instruct that these solutions be labeled with the appropriately determined “use by” or expiration date upon preparation and discarded upon expiration.

These principles would also apply to API manufacturing and testing sites. The use of “reagents and solutions” and “use by” dates are found throughout Guidance for Industry: Q7, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.

FDA Current Good Manufacturing Practice for Finished Pharmaceuticals regulations at 21 CFR 211.160 and 211.194

  • 211.160
  • 211.194

FDA Guidance for Industry

Contact for further information:
Mr. Brian Belz, Compliance Officer
CDER/OC/OMPQ/DIDQ/International Compliance

FDA Guidance for Drug Components at Risk for Contamination

FDA issued the subject guidance document in August 2009 to address the potential risk of melamine contamination in pharmaceutical components. This may seem like old news, but with the focus on the supply chain, there is more and more responsibility being placed on the finished drug manufacturer to ensure the incoming quality of components and the outgoing quality of the drug product. FDA considers the presence of melamine in a drug to render that drug adulterated. Melamine contamination was responsible for the tainted pet food incident in 2007 and the contaminated infant formula tragedy in China in 2008. FDA is suggesting that industry determine if their components are at risk, and if so, that the manufacturer of finished drug product test for melamine contamination using methods recommended by FDA.

Read more about these methods here.

FDA expects manufacturers to know and monitor their supply chain and obtain certification from at risk component manufacturers that the components have been tested for the absence of melamine contamination.

This guidance document has a list of at risk components, that is not all inclusive, and still requires manufacturers to perform risk assessment of their components on an individual basis.

Download the guidelines (pdf).

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.