Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs

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FDA released the following Guidance Document, effective April 2012: Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs.

This guidance is intended to help manufacturers of positron emission tomography (PET) drugs meet the requirements for the Agency’s current good manufacturing practice (CGMP) regulations for PET drugs (21 CFR part 212). Most PET drugs are designed for parenteral administration and are produced by aseptic processing.

Additionally, until June 12, 2012, FDA does not intend to take enforcement action against a PET facility currently producing PET drugs for clinical use for a failure to submit a new drug application by December 12, 2011, provided that the facility complies with all other FDA requirements, including current good manufacturing practices (CGMPs). FDA will not exercise enforcement discretion after June 12, 2012. Therefore, if a facility wishes to continue to produce PET drugs for clinical use after June 12, 2012, they must have submitted a new drug application (NDA) or an abbreviated new drug application (ANDA) by that date, or be producing the drugs under an investigational new drug application (IND).

Read the guidance here.

“Risk takes a new dimension” : PIC/S Aide-Memoire

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Effective 2 April 2012, PIC/S (Pharmaceutical Inspection Cooperation Scheme) published an Aide-Memoire for GMP inspectors on inspections of quality risk management (QRM) systems. The document defines what companies can expect GMP inspectors to be looking for regarding risk management. The document is based on ICH Q9: Risk Management. There are 5 sub-chapters that address:

  1. Overall Systems: does the company use a Quality Risk Management approach, is Senior Management involved in the process, and if there are issues, does Senior Management take action?
  2. Expectations on how QRM should be implemented: Is the process scientific based and does it take prior experience into consideration, and have staff been trained on risk management tools?
  3. Specific Areas and Activities where Implementation of QRM might be expected: QRM would be expected in many areas of the quality system, like, deviations, OOS, CAPA, complaints, change control, sampling and testing, supplier qualification, validation, audit program, etc.
  4. Review of Residual Risk: This addresses assessing the effectiveness of the risk decisions and plans if additional information is forthcoming. This section references ICH Q10 as the model for management review.
  5. Review and improvement of QRM activities: does the company periodically review the QRM system as part of management review and to promote continual improvement of the system?

Read the documentation here.

Changes to CGMPs for Human and Veterinary Drug Products

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The following is excerpted from the attachment and summarizes the changes to the CGMPs. This is a significant change to the GMPs and reflects FDA’s confidence in automated technology as well as their risk management approach to patient safety.

Food and Drug Administration (FDA) is amending the packaging and labeling control provisions of the current good manufacturing practice (CGMP) regulations for human and veterinary drug products by limiting the application of special control procedures for the use of cut labeling to immediate container labels, individual unit cartons, or multiunit cartons containing immediate containers that are not packaged in individual unit cartons. FDA is also permitting the use of any automated technique, including differentiation by labeling size and shape that physically prevents incorrect labeling from being processed by labeling and packaging equipment when cut labeling is used. This action is intended to protect consumers from labeling errors more likely to cause adverse health consequences, while eliminating the regulatory burden of applying the rule to labeling unlikely to reach or adversely affect consumers. This action is also intended to permit manufacturers to use a broader range of error prevention and labeling control techniques than permitted by current CGMPs.

Read the full text here.

New & Revised Draft Guidances from CDER coming in 2012

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On March 6, 2012, FDA’s Center for Drug Evaluation and Research (CDER) published a Guidance Agenda listing the new and revised draft guidance documents CDER plans to publish during 2012. There are over 50 guidances planned. We will have a busy year reading, understanding and complying with these new and revised guidances. Welcome to the 21st century! Let MWA know how we can assist you with your compliance needs.

Read the complete guidance agenda here.

FDA Issues Draft Guidance on Post Approval Drug Safety Issues

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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​on (WHO)

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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

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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?

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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

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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

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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.