NEWS

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

Posted on

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.

References:
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
brian.belz@fda.hhs.gov

FDA Guidance for Drug Components at Risk for Contamination

Posted on

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

Posted on

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

Posted on

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

Posted on

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

Posted on

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

Posted on

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

Posted on

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

Posted on

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

Posted on

“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