SQA Regulatory Surveillance Summary | Monthly Update 2022 – June
By Laurel Hacche & Debra Cortner SQA Associates
SQA Regulatory Surveillance Summary 2022 – June
Agência Nacional de Vigilância Sanitária (ANVISA)
ANVISA published the RDC 702/2022, which repeals some requirements that were instituted to speed market approval of devices needed to treat patients during the height of the COVID-19 pandemic. Resolution RDC 702/2022 became effective on 22 May 2022 and repeals the following:
- RDC 349/2020: the temporary criteria and procedures for regularization of personal protective equipment (PPE), ventilators and other medical devices ANVISA identified as critical to the PHE.
- RDC 375/2020: extraordinary/temporary procedures for submission of clinical trials used for the validation of class III and IV medical devices due to PHE.
- RDC 378/2020: temporary procedures for import of used ICU equipment due to PHE.
- RDC 386/2020: assembly, sale and donation of Artificial Manual Breathing Unit (AMBU) devices.
- RDC 445/2020: special consent for retroactive application of extended shelf life for IVD devices.
- RDC 448/2020: temporary requirements for manufacture, import and sale of priority PPE.
ANVISA, Brazil’s medical device market regulator, has expanded quality management system certification requirements to additional types of manufacturing units for some higher-risk products.
According to ANVISA’s RDC 687/2022 (link in Portuguese), Brazilian Good Manufacturing Practice (BGMP) certification will be required for the following manufacturing units for Class III and Class IV devices:
- Manufacturing units producing final products either on their own behalf or for other companies
- Manufacturing units performing final releases of final products and that are involved in at least one stage of production other than design, distribution, sterilization, packaging or labeling stages
- Manufacturing units for software as a medical device (SaMD)
Affected manufacturers have until 28 November 2022 to comply with the ANVISA BGMP certification requirements.
China: National Medical Products Administration (NMPA)
On 09 May 2022, NMPA released the draft of the revised Regulations for Implementation of the Drug Administration Law (hereafter referred to as the Regulations) for public comments. The Regulations were first issued with immediate effect in 2002 and were later revised in 2016. Compared to the 2016 revised version, the draft of the 2022 version includes 101 more articles to conform to the pharmaceutical policy reforms in the recent years and the Drug Administration Law revised in 2019. The new contents involve marketing authorization holder system, patent protection, and pharmacovigilance, whose regulations just came out in the past few years.
On 27 May 2022, NMPA released the Appendix to Good Manufacturing Practice (GMP) for Pharmaceuticals: Investigational Products Used in Clinical Trials, which will take effect on 01 July 2022. The appendix gives more detailed GMP requirements for the preparation of investigational products. The appendix applies to:
- The preparation of investigational products used in clinical trials, including the investigational drugs being tested or the comparator drugs/placebos used as a reference
- The clinical trials aim for China’s marketing authorization of the investigational drugs
- Changes to packaging/labels of marketed drugs that are used as comparator drugs or investigational drugs
- Adding correctants to comparator drugs for blinded experiments.
The Appendix is also a reference for active pharmaceutical ingredients (API) used in investigational products.
Eudralex, Volume 4: GMP Guidelines and Annexes
The final version of Annex 21 to the EU-GMP Guidelines (“Importation of medicinal products”) has been published in Eudralex Volume 4. The draft was already published for comments in March 2020. Approximately 200 comments were received from 17 stakeholder organizations. The new Annex will come into operation on 21 August 2022. Changes from the original draft are as follows:
- Explicitly included are now Investigational Medicinal Products (IMPs). Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products that do not have a marketing authorization in the EU/EEA and are directly re-exported were not included.
- “Fiscal transactions” (where the product physically remains in the EU but changes ownership to a third country or vice versa) remain explicitly excluded.
- The complete batch documentation must be available to the Manufacturer’s/Importation Authorization (MIA) holder responsible for QP certification or batch confirmation at the time of certification or batch confirmation. In the draft, this was still stated as “should have access”.
- For QP certification or batch confirmation, a packing list, freight documentation or a customs import declaration, is now also required. The certification of a batch can therefore only take place after physical importation and customs clearance.
European Commission (EC)
A European Commission working group has published new guidance on distinguishing between medical devices and medical products under the Medical Devices Regulation (MDR). The new guidance from the European Medical Device Coordination Group (MDCG) covers “borderline products” not easily categorized either as medical devices falling under MDR requirements or medical products for human use falling under Directive 2001/83/EC (MPD) requirements for CE Marking. How a borderline product is defined helps determine whether that product must comply with the MDR or MPD, according to the MDCG guidance.
- Borderline products must meet the MDR definition and scope of a medical device or accessory to a medical device to fall under the Regulation’s requirements
- Products must meet MPD definitions of a medical product to meet 2001/83/EC requirements:
- Any substance or combination of substances with properties for treating or preventing disease
- Any substance used in human beings to restore, correct, or modify physiological functions via pharmacological, immunological or metabolic means
Because both medical devices and medical products may be intended to treat or prevent disease, the guidance identifies the “principal mode of action” as the key factor for distinguishing between a medical device and a medical product. In cases where a particular borderline product exhibits characteristics of both a medical device and a medical product, MPD provisions and requirements ultimately apply. The MDR and the MPD may not be applied cumulatively.
A Mutual Recognition Agreement (MRA) aligning in vitro diagnostic (IVD) regulations between the European Union and Switzerland has officially expired following the In Vitro Diagnostic Medical Devices Regulation’s (IVDR) 26 May 2022 date of application, impacting certification and authorized representation requirements for manufacturers. The European Commission has issued new guidelines covering how the expired MRA affects IVD manufacturers now that the IVDR has taken effect in Europe and the Ordinance on In vitro Diagnostic Medical Devices (IvDO) has come into force in Switzerland. As became the case in May 2021, when the European Medical Devices Regulation (MDR) came online without an updated MRA between the EU and Switzerland, Swiss manufacturers of IVDs are now treated as any other “third country” manufacturers seeking CE Marking to sell their devices in the EU. Third-country designation affects CE Mark certification as well as Authorized Representation requirements. This means that new IVDs developed by Swiss manufacturers must undergo EU Conformity Assessment Body (CAB) review and certification. Furthermore, existing certificates issued under the erstwhile MRA for IVDs by CABs in Switzerland (even those issued before 26 May 2022) are in many cases no longer valid in the EU.
European Medicines Agency (EMA)
This Question and Answer document provides guidance and seeks to support sponsors, clinical trialists and applicants regarding scientific aspects and the planning, set-up, submission for obtaining Clinical Trial Authorization (CTA), conduct, reporting and transparency, analysis and interpretation of Complex Clinical Trials (CCTs) under the EU Clinical Trials Regulation (EU CTR) as well as their use in submissions for marketing authorization. It complements and should be used together with relevant EU and ICH guidelines, in particular E6, E8, E9, E10, E16, E19, E11A and E20 (when available). For the purpose of this document, the nomenclature follows the EU CTR, relevant ICH guidance, the Clinical Trials Facilitation and Coordination Group (CTFG) Recommendation Paper on the Initiation and Conduct of Complex Clinical Trials (2019), and international common use as appropriate. Additional non-binding terminology conventions are described in the glossary to facilitate alignment between different sources of information and ensure consistent meaning.
Marketing authorization holders (MAHs) can now register their Industry Single Point of Contact (i-SPOC) who will inform EMA about the supply and availability of critical medicines identified in the context of a ‘public health emergency’ or a ‘major event’. Regulation (EU) 2022/123 reinforces EMA’s role in crisis preparedness, including the monitoring and management of medicine shortages that may lead to a crisis and, during a public health emergency or a major event, with the reporting of shortages, information on supply and demand, and coordinating responses of EU countries to shortages of critical medicines. All pharmaceutical companies with a centrally-or nationally-authorized medicinal product in the EU are required to register a single point of contact. The i-SPOC will facilitate rapid communication between EMA and MAHs to detect, report, and prevent or manage supply and availability issues of medicines included in a list of critical medicines for a ‘public health emergency’ or a ‘major event’. The Agency recently published the first list of critical medicines for the management of the COVID-19 pandemic. Registration of an i-SPOC is a two-step process which may take up to 5-10 working days. EMA has updated the IRIS user guide to support companies with the registration process. Companies must register their i-SPOC in EMA’s IRIS online platform by 02 September 2022.
European Pharmacopoeia (Ph. Eur.)
The European Pharmacopoeia (Ph. Eur.) Commission held its 173rd session on 21 and 22 June 2022. Forty-eight texts were adopted and will be published in Ph. Eur. Supplement 11.2, effective as of 01 July 2023. Of these 48 texts, four were new monographs: Pumpkin seed (2941), Propylene Glycol Monocaprylate (2799), Mirabegron (3132) and Saxagliptin Monohydrate (3136). The remaining 44 were revisions and included:
- A total of six (6) monographs on excipients were revised to include a Functionality-Related Characteristics (FRC) section and two (2) others whose FRC section had been updated. As of Supplement 11.2 and with these 6 additions, the Ph. Eur. will contain more than 100 excipient monographs with an FRC section supporting the definition of critical material attributes for specific applications.
- A revised version of the general monograph onMonoclonal Antibodies for Human Use (2031), to ensure alignment with the dosage form monograph Parenteral Preparations (0520) with regard to visible particles. The revised monograph now refers directly to new general chapter 17.2. Recommendations on Testing of Particulate Contamination: Visible particles and includes the requirement ‘practically free from visible particles’ for liquid parenteral preparations, together with recommendations on testing for visible particles.
- A total of four (4) monographs on Somatropin were revised to harmonise their content. In particular, the analytical procedure capable of detecting additional oxidised forms already included inSomatropin Injection (2370) was also introduced in Somatropin Concentrated Solution (0950), Somatropin (0951) and Somatropin Powder for Injection (0952). In combination with the Capillary Zone Electrophoresis (CZE) detection of deamidation forms, this approach offers a superior control of the related proteins in somatropin.
For more information, read the press release “Outcome of the 173rd session of the European Pharmacopoeia Commission, June 2022”.
At its 173rd session, the European Pharmacopoeia Commission approved the publication of a new edition of the Technical Guide for the elaboration of monographs. This guide is an essential aid both to the drafting of monographs and for the transposition of analytical techniques into a pharmacopeial procedure. It helps ensure a high level of harmonization throughout the texts of the Ph. Eur., all of which are written by the experts of the different groups and, together with the Style Guide, can also serve more widely as a means of better understanding the requirements, format, and set-up of a monograph. With the previous version of the Guide dating back to 2015, it was clear that a substantial overhaul of the text would be necessary to incorporate the technical progress and new policies that have been adopted in the intervening years. The 8th edition of the Technical Guide, as recently approved by the Ph. Eur. Commission, therefore contains all-new sections in addition to the existing parts, now comprehensively updated, to reflect these changes. The revision of the General Notices(1.), the implementation of the general chapter Balances (2.1.7) and the harmonization of the general chapter, Degree of coloration of liquids (2.2.2), prompted several editorial and technical modifications, with other changes, such as the switch to a molecular sieve from phosphorous pentoxide in the revised general chapter Loss on drying (2.2.32), also now reflected. This revised technical guide also applies to medicinal product monographs, where appropriate, and a reference to the Technical Guide on elaboration of monographs on medicinal products containing chemically defined active substances has been included as a footnote.
International Society for Pharmaceutical Engineering (ISPE)
The ISPE Good Practice Guide: Membrane-Based Water for Injection Systems provides expert guidance on the design, operation, maintenance, and quality aspects of membrane-based WFI systems, including generation, storage, and distribution. This Guide reflects an industry wide collaborative effort by a diverse range of industry experts that include equipment providers, engineering firms, consultants, and pharmaceutical manufacturers. The information presented in this guide is the combination of proven technological solutions, microbial control methods, process analytical technology, and operations and maintenance practices. This Guide is a complementary guide to several other ISPE Guidance Documents as indicated below. It is recommended that the readers have a baseline knowledge of pharmaceutical water systems and their unit operations prior to reading this Guide.
- ISPE Baseline Guide: Volume 4 – Water and Steam Systems (Third Edition)
- ISPE Good Practice Guide: Approaches to Commissioning and Qualification of Pharmaceutical Water and Steam Systems
- ISPE Good Practice Guide: Critical Utilities GMP Compliance
- ISPE Good Practice Guide: Ozone Sanitization of Pharmaceutical Water Systems
United States Food and Drug Administration (FDA) – Regulations and Guidances
On 10 May 2022, the FDA’s Center for Drug Evaluation and Research (CDER) released for public comment Benefit-Risk Considerations for Product Quality Assessments: Guidance for Industry. The purpose of this guidance is to describe the benefit-risk principles applied by the FDA when conducting product quality-related assessments of Chemistry, Manufacturing, and Controls (CMCs) when information is submitted to the FDA for an assessment as part of original New Drug Applications (NDAs), original Biologics License Applications (BLAs), or supplements to NDAs or BLAs, in addition to other information available (enforcement actions, adverse reactions, recalls, etc.). This guidance discusses how the FDA considers and assesses risks, sources of uncertainty, and possible mitigation strategies for product quality-related issues and how unresolved product quality issues may be addressed. The FDA uses product quality assessments to determine whether an applicant’s product development studies, manufacturing process, and process control strategy will consistently result in finished product of acceptable quality. The FDA considers the overall benefit(s) and risk(s) identified for the product, including any residual risk related to unresolved product quality issues, regarding the regulatory approval of an NDA or BLA.
The FDA is announcing the availability of a draft guidance for industry entitled Conducting Remote Regulatory Assessments, Question and Answers. The FDA is issuing the draft guidance to describe the Agency’s current thinking regarding its use of Remote Regulatory Assessments (RRAs) to increase industry’s understanding of RRAs and facilitate FDA’s process for conducting RRAs. FDA has used RRAs to conduct oversight, mitigate risk, meet critical public health needs, and help maximize compliance of FDA-regulated products. This draft guidance provides answers to frequently asked questions regarding what RRAs are, when and why FDA may use them, and how FDA may conduct them, among others.
FDA is announcing the availability of a draft guidance for industry entitled DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs. This guidance identifies the standards necessary to facilitate adoption of secure, interoperable, electronic data exchange among the pharmaceutical distribution supply chain, and clarifies the trading partners, products, and transactions subject to such standards. This guidance is a revision of the draft guidance for industry entitled DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs: How to Exchange Product Tracing Information, issued in November 2014 as required by the Federal Food, Drug, and Cosmetic Act (FD&C Act).
United States Food and Drug Administration (FDA) – Recalls
Plastikon Healthcare, LLC is voluntarily recalling one (1) lot of Milk of Magnesia 2400 mg/10 mL Oral Suspension, one (1) lot of Milk of Magnesia 2400 mg/30 mL Oral Suspension, eleven (11) lots of Magnesium Hydroxide 1200 mg/Aluminum Hydroxide 1200 mg/Simethicone 120 mg per 30 mL Oral Suspension, and two (2) lots of Magnesium Hydroxide 2400 mg/Aluminum Hydroxide 2400 mg/Simethicone 240 mg per 30 mL Oral Suspension to the consumer level. The products are being recalled due to microbial contamination. Product indication, lot numbers, expiration dates, and NDC information are provided on the FDA website. The products are packaged for institutional use and are sold to clinics and hospitals nationwide in single use cups with a foil lid. The affected lots were distributed to Major Pharmaceuticals Distribution Center (wholesaler) between 01 July 2020 and 31 October 2021, who shipped to hospitals, nursing homes, and clinics nationwide. The products are private labeled for Major Pharmaceuticals.
Risk Statement: Administration or use of oral drug products with microbial contamination could potentially result in increased infections that may require medical intervention. Patients with compromised immune systems, such as patients in hospitals and nursing homes, have a higher probability of developing potentially life-threatening infections after taking a contaminated product. To date, Plastikon Healthcare has not received any reports of adverse events or injuries related to this recall.
BD (Becton, Dickinson and Company), a leading global medical technology company, announced a voluntary recall on the BD™ Intraosseous Needle Set Kits, BD™ Intraosseous Manual Driver Kits and BD™ Intraosseous Powered Drivers. Certain lots within the expiration date of these intraosseous products may result in delays in care due to limited or non-functioning intraosseous access or could also lead to needlestick injuries. Customers should immediately review their inventory for the catalog and lot numbers listed above. Affected needle kits should be destroyed in compliance with the health care institution’s process for disposal. The use of affected intraosseous powered drivers should be paused until a BD representative provides instruction that it is safe for use. BD representatives will be reaching out to customers for inspection and will repair the devices if required. There are no replacement products currently. BD recommends that customers evaluate their clinical needs and consider obtaining and using an alternative intraosseous product. BD will notify customers when replacement products become available.
Bryant Ranch Prepack Inc. is voluntarily recalling one lot of Morphine Sulfate 30 mg Extended-Release tablets (Comprised of 10 bottles), and one lot of Morphine Sulfate 60 mg Extended-Release tablets (Comprised of 10 bottles) to the consumer level. The products have been found to have incorrect labeling where bottles labeled as Morphine Sulfate 60 mg Extended-Release tablets contain Morphine Sulfate 30 mg Extended-Release tablets and bottles labeled as Morphine Sulfate 30 mg Extended-Release tablets may contain Morphine Sulfate 60 mg Extended-Release tablets.
Risk Statement: Patients prescribed the 30 mg dose who receive the 60 mg dose could be at risk for overdose and death. Patients prescribed the 60 mg dose who receive the 30 mg dose may experience withdrawal and untreated pain if the dose given is too low. To date, Bryant Ranch Prepack Inc. has not received any reports of adverse events related to this recall.
United States Food and Drug Administration (FDA) – Warning Letters
During an inspection of Re-Gen Active Lab, Inc. in Irving, TX, conducted between 19 July 2021 and 28 July 2021, the FDA documented the manufacture of cellular products for allogeneic use, namely, an amniotic membrane derived cellular product, ActiveFlow™, a human umbilical cord tissue derived cellular product, ActiveShot™, and a cellular product derived from both human umbilical cord tissue and amniotic membrane, ActivePro™. These products have been distributed directly to a third-party distributor, physicians, and medical clinics throughout the United States. These products are intended for injection and are purported to be sterile. At the close of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described significant deviations applicable to Re-Gen Active Lab, Inc. products. Form FDA-483 observations were related to the following:
- Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of the aseptic process.
- Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, that are used in the manufacture, processing, packing and holding of a drug product, according to a written program designed to assure proper performance.
- Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product.
- Failure to establish written procedures describing in sufficient detail the cleaning methods, equipment, and materials to be used in cleaning the buildings and facilities
- Failure to establish written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.
- Failure to satisfy general biological products standards for sterility testing.
- Failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval or rejection of components and drug product containers and closures.
- Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use the results of such stability testing to determine appropriate storage conditions and expiration dates.
- Failure to prepare batch production and control records for each batch of drug product produced that include complete information relating to the production and control of each batch, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished.
FDA has issued a Warning Letter to the Elite Training Facility on 06 July 2022 stating that the FDA has reviewed the company’s website at the Internet address https://www.elitesupplementcenter.com/ in June 2022 and has observed that the Elite Training Facility take orders there for Ostarine MK-2866, Ligandrol LGD 4033, Ibutamoren MK-677, Testolone Rad140, and Cardarine GW501516 and that these products are marketed on the product labels as Selective Androgen Receptor Modulators (SARMs). FDA has safety concerns about products that contain SARMs. Life-threatening reactions, including liver toxicity, have occurred in people taking products containing SARMs. SARMs also have the potential to increase the risk of heart attack and stroke. Despite statements on product labels marketing the SARMs products for “RESEARCH ONLY” and “Not for Human Consumption,” evidence obtained from the website establishes that the products are intended to be drugs for human use. This FDA Warning Letter notifies the Elite Training Facility of the above concerns and provides the company with an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure, and injunction.
United States Pharmacopeia (USP)
- Updated Notice of Intent to Revise:<711> Dissolution (posted 27-May-2022; updated 29-Jul-2022)
- New Notice of Intent to Revise: Rifabutin (posted 29-Jul-2022)
- Updated General Chapter Prospectus:<1568> Quality Considerations for Cannabis and Cannabis-derived Products for Clinical Research (updated 30-Jun-2022; input deadline 31-Jul-2022)
- New Notice of Intent to Revise: Upcoming Changes to USP’s Description and Relative Solubility Reference Table (posted 24-Jun-2022)
- New General Chapter Prospectus:<1154> Liposome Drug Products (posted 24-Jun-2022; input deadline 24-Jul-2022)
- New General Announcement: USP General Notices Biologics Nomenclature (posted 06-Jun-2022)
- New Notice of Intent to Revise: Isotretinoin Capsules (posted 27-May-2022)
- New Notice of Intent to Revise: Ziprasidone Hydrochloride (posted 27-May-2022)
- New Notice of Intent to Revise: Phenelzine Sulfate (posted 29-Apr-2022)