SQA Regulatory Surveillance Summary | Monthly Update 2022 – September/October
SQA Regulatory Surveillance Summary for September and October 2022
Agência Nacional de Vigilância Sanitária (ANVISA)
ANVISA published answers to questions received during an online seminar on clinical research of medicinal cannabis held in May 2022. The 20-page Q&A document covers general and specific topics including the importation of cannabis products, simplified authorization procedures for education, and research institutions that are conducting cannabis studies using real-life data. One of the important questions addressed is: How can batch reproducibility be demonstrated?
Brazil’s ANVISA Announces Major Medical Device Registration Updates, 16 September 2022
ANVISA announced major updates to its Resolution of the Collegiate Board of Directors (RDC) 185/2001. The changes will serve to strengthen the country’s medical device registration regulations upon their effective date of 01 March 2023. The new regulation, RDC 751/2022 (link in Portuguese), further defines the rules for classifying the risk of medical devices, requirements for labeling, instructions for use, and the procedures for notification or registration of medical devices.
China: National Medical Products Administration (NMPA)
The CMDE published new guidance (link in Chinese) for medical device registration applicants. This guidance will help applicants interpret how to implement Essential Principles of Medical Device Safety and Performance using information that was issued in March 2020. CMDE Announcement No. 29 of 2022, Technical Guidelines for Compliance with the Essential Principles of Medical Device Safety and Performance. These guidelines were created to help medical device manufacturers integrate the requirements of the regulation into the development and manufacture of medical devices. Notably, the guidelines identify applicable products and methods to demonstrate compliance for each section of the Essential Principles.
The CMDE published additional documents (link in Chinese) that outline the recommended paths for clinical evaluation of certain devices under select sub-categories of the Medical Device Classification Catalog. CMDE Announcement No. 30 of 2022, Recommended Clinical Evaluation Paths for Certain Medical Devices, which serves to guide registration applicants in determining the clinical evaluation path for the following products:
- 01 Active Surgical Instruments
- 04 Orthopedic Surgical Instruments
- 07 Medical Diagnostic and Monitoring Equipment
- 08 Respiration, Anesthesia and First Aid Devices
- 09 Physiotherapy Equipment
- 10 Blood Transfusion, Dialysis and Cardiopulmonary Bypass Devices
- 19 Medical Rehabilitation Equipment
- 21 Medical Software
For guidance on using these documents, the CMDE also published Instructions for Use of the Recommended Path for Clinical Evaluation of Related Products for each subcategory. For details, these documents are provided as attachments to CMDE Announcement No. 30 of 2022.
Class I Medical Device Filing Rules, Unique Device Identifier (UDI) Standards, 18 August 2022
NMPA has amended guidance on record filing requirements for low-risk Class I medical devices to reflect broader updates to medical device and In Vitro Diagnostic (IVD) regulations and has also identified relevant standards for China’s UDI system. NMPA’s record filing changes under Announcement No. 62 of 2022 (link in Chinese) include the following details that should be of interest to Class I medical device market registrants in China:
- Simplified filing requirements that no longer include items such as risk analysis reports or clinical evaluation reports.
- Additional requirements for details including product name and description, intended use and model/specification.
- Issuance of a device filing number via a “Notification of Filing Number,” which replaces the current Filing Certificate.
The NMPA’s revisions to Class I device record filing rules replaces the regulator’s Announcement No. 26 of 2014. NMPA has also compiled a list of relevant standards (link in Chinese) to support UDI of medical devices. Standards identified by the NMPA include:
- Basic Requirements for Unique Identification of Medical Devices
- Database Basic Data Set for Unique Identification of Medical Devices
- Guidelines for Reporting in the Database of Unique Identification of Medical Devices
- Basic Terms for the System of Unique Identification of Medical Devices
EudraLex, Volume 4: GMP Guidelines and Annexes
Finalized: The Revised EudraLex, Annex 1, Manufacture of Sterile Medicinal Product, 22 August 2022
The European Commission (EC) decided to revise the EudraLex, Annex 1, Manufacture of Sterile Medicinal Products to cover the current regulatory and technological developments in the manufacture of sterile medicinal products. In particular, the integration of ICH Guidelines Q9: Quality Risk Management, Q10: Pharmaceutical Quality System, and the inclusion of new technological developments made the revision of Annex 1 imperative. The EC presented a first draft for public comment to the revision of Annex 1 in 2017. More than 6,000 comments led, quite unusually, to a second draft for renewed public comment in 2020. Long awaited, the final version of Annex 1 was published on 25 August 2022. The new Annex 1 will begin on 25 August 2023 with the exception that the deadline for Chapter 8.123, “Product transfer/ loading/unloading areas for lyophilizers” is 25 August 2024.
European Commission (EC)
The Proposal for a Regulation on the Safety and Quality of Substances of Human Origin (SoHO) is another building block of the European Health Union. It will promote pooling resources and achieving economies of scale. Its ambition is to create more opportunities for patients across the European Union (EU) to access the treatment they need independently of where they live. It will also facilitate cross-border circulation of these critical health therapies as well as cross-border cooperation between public health authorities. It reinforces solidarity, while ensuring the same harmonized high-level standards of quality and safety for all SoHO. The proposal updates and reinforces the rules for safety and quality and extends them to other substances of human origin (SoHO), such as human breast milk, which were previously left unregulated at EU level. The result is a proposal for a future-proof and robust framework which better protects donors, recipients treated by transfusion, transplantation or medically assisted reproduction, and offspring born from donated sperm or eggs. It also fosters innovation in this crucial biotech sector. This proposal builds upon the existing legal framework, which came into force in 2002 for blood and 2004 for tissues and cells. The framework contains parallel provisions for donor selection, quality and safety management and oversight. While this regulation will bring a high level of safety and quality standards, it still leaves Member States the possibility to add more stringent requirements to ensure alignment to the set-up of national healthcare systems.
European Medicines Agency (EMA)
EMA Launches Pilot Project on Analysis of Raw Data from Clinical Trials, 12 July 2022
The EMA has launched a pilot project to assess whether the analysis of raw data from clinical trials by regulatory authorities improves the evaluation of Marketing Authorization Applications (MAAs) for new medicines as well as post-authorization applications. This project also explores the practical aspects of the submission and analysis of such data. Raw data constitutes individual patient data from clinical studies in electronic structured format that is directly accessible for analysis and visualization. Examples of raw data include records of original observations and measurements of clinical study participants, such as clinical laboratory results, imaging data, and patient medical charts. Currently, the European medicines regulatory system does not routinely require the submission of raw data in the context of a marketing authorization or post-authorization application. The EMA’s Committee for Medicinal Products for Human Use (CHMP) receives data submitted by the applicant or Marketing Authorization Holder (MAH) after statistical processing in aggregated format as clinical summaries, as well as in PDF listings. The CHMP scrutinizes these summaries as part of the scientific evaluation for the benefits and risks of medicinal products. Raw data have been requested by the CHMP on several occasions when it was considered to be helpful in the evaluation of a medicinal product. The pilot project is open to applicants or MAHs that are about to submit MAAs or post-authorization applications. If selected, they will include raw data as part of their submissions. The pilot is expected to last up to two years and will include approximately 10 regulatory procedures submitted to EMA from September 2022. The pilot will fully comply with data protection legislation requirements. Applicants and MAHs can contact EMA via rawdatapilot@ema.europa.eu to express their interest in participating or to gather more information.
EMA Publishes Guidance on Preventing Medicine Shortages, 15 July 2022
EMA has published a guidance for patients and healthcare professional organizations with key principles and examples of good practices to support them in preventing and managing shortages of human medicines. Medicine shortages and reduced availability of medicine represent an increasing issue across the European Union (EU) and the globe, which has been amplified by the COVID-19 pandemic. It may have a significant impact on patient care by causing medicine rationing and delay of critical treatments. Due to medicine shortages, patients may need to use fewer effective alternatives and could risk using medication incorrectly. The causes of shortages can include manufacturing problems leading to delays, interruption in production, shortages of raw materials, increased demand of medicines, distribution problems, labor disruptions, and natural disasters. Patients and healthcare professionals are the main actors at the end of the supply chain; therefore, their activities are usually limited to managing the demand for medicines at risk of shortages. The EMA guidance also looks at measures that help to improve preparedness, planning, and rationed use for medicines that are either in short supply or expected to be so soon. Some of the key recommendations included in the EMA guidance apply only to patients’ organizations, some only to healthcare professionals’ organizations, and some to both. For example, both types of organizations are encouraged to:
- Develop observatories in collaboration with national authorities to collect and analyze information from patients and healthcare professionals on shortages and their early signs.
- Work with national authorities on criteria and ways to develop registries of essential and critical medicines.
- Set up campaigns across the EU to raise awareness of shortages, where to find information on ongoing shortages, risks of stockpiling, and safe use of alternative medicines.
European Pharmacopoeia (Ph Eur)
General chapter 2.2.46. Chromatographic Separation Techniques has been revised to incorporate the provisions of the pharmacopeial harmonization text, signed-off by the Pharmacopeial Discussion Group (PDG) on 28 September 2021. The revised chapter is now available in the 11th Edition of the Europe Pharmacopoeia (Ph. Eur. 11.0, implementation date: 01 January 2023). This general chapter applies to chromatographic analytical procedures and supplements the following:
- General Chapter 2.2.7. Thin Layer Chromatography
- General Chapter 2.2.28. Gas Chromatography (GC)
- General Chapter 2.2.29. Liquid Chromatography (LC)
- General Chapter 2.2.30. Size-exclusion chromatography
In addition to definitions of chromatographic features, the revision to General Chapter 2.2.46. contains system suitability requirements for LC and GC procedures, complementing those given in the individual monographs.
11th Edition of The European Pharmacopoeia Now Available in Print, 17 August 2022
The European Directorate for the Quality of Medicines & HealthCare (EDQM) is pleased to announce the release of the print version of the 11th Edition of the Ph Eur. This latest edition contains numerous revised and new texts that reflect the latest scientific and technological progress and regulatory developments in the quality control and safety of medicinal products and their constituents. With a total of 2,469 monographs, 386 general texts and more than 2,800 descriptions of reagents, the 11th Edition offers new additions such as:
- General Chapter 2.7.26. Cell-Based Assay for Potency Determination of TNF-Alpha Antagonists, the landmark first ‘horizontal’ or ‘performance-based’ standard for monoclonal antibodies that was elaborated in response to stakeholder demand.
- General Chapter 5.26. Implementation of Pharmacopeial Procedures, providing more detailed practical information on one of the key processes underpinning the correct use and application of Ph. Eur. texts.
- General Chapter 2.2.46. Chromatographic separation techniques, chromatography being one of the most widely used techniques in analytical quality control. This is a significant accomplishment and signifies the successful outcome of global quality standard convergence efforts involving the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP) and the Ph Eur.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance’s – Quality, Efficacy, Multidisciplinary, and Safety
ICH Advances Guidelines on Selective Reporting of Safety Data, Viral Safety, 11 October 2022
ICH Harmonized Guideline E19, A Selective Approach to Safety Data Collection in Specific Late-State Pre-Approval or Post-Approval Clinical Trials was adopted on 27 September 2022. This guideline is intended to provide internationally harmonized guidance on the use of selective safety data collection that can be applied to specific late-stage clinical trials that are in pre-approval or post-approval. Selective safety data collection refers to the reduced collection of certain types of data in a clinical trial after thorough consideration of factors that would justify such an approach. By tailoring the method of safety data collection, it may be possible to conduct clinical trials with greater efficiency by streamlining the approach to data collection. This may facilitate the conduct of large-scale efficacy and safety clinical trials with large numbers of participants and long term follow ups. In all circumstances that the use of selective safety data collection is considered, the welfare of every trial participant should be safe guarded.
ICH has announced that its Q5A(R2) guideline that sets harmonized scientific and technical requirements for testing the viral safety of biotechnology products, has reached Step 2 of the ICH process. The guidance covers cell line qualification and testing for viruses, testing for viruses in unprocessed bulk, the rationale and action plan for viral clearance studies, virus testing on purified bulk, evaluating, and characterizing viral clearance procedures, and points to consider for continuous manufacturing processes.
International Society for Pharmaceutical Engineering (ISPE)
GAMP 5 Guide, 2nd Edition, July 2022
GAMP aims to deliver a cost-effective framework of good practice to ensure that computerized systems are effective, of high quality, fit for intended use, and compliant with applicable regulations. Maintaining the principles and framework of the first edition, ISPE GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems, Second Edition updates their application in the modern world including the increased importance of service providers, evolving approaches to software development, and the expanded use of software tools and automation. It highlights the use of critical thinking by knowledgeable and experienced Subject Matter Experts (SMEs) to define appropriate approaches. The ISPE GAMP Community of Practice (CoP) performs regular ongoing assessments and reviews of GAMP knowledge against current practices and regulatory and technology developments. ISPE GAMP 5, Second Edition therefore embraces and reflects:
- Increased importance of service providers, which includes encouraging regulated companies to maximize supplier involvement to leverage knowledge, experience, and documentation where possible.
- Evolving approaches to software development, emphasizing that the GAMP specification and verification approach is not inherently linear but also fully supports iterative and incremental methods.
- Increased use of software tools and automation to achieve greater control, higher quality, and lower risks throughout the life cycle.
APQ Guide: Process Performance & Product Quality Monitoring System (PPPQMS), September 2022
The ISPE APQ Guide: Process Performance and Product Quality Monitoring System (PPPQMS) provides a quality management framework for assessing and advancing an organization’s PPPQMS maturity level by evaluating the following aspects:
- Establishing a Control Strategy
- Determining Tools for Measurement and Analysis of Parameters and Attributes
- Analyzing Parameters and Attributes
- Identifying Sources of Variation
- Including Feedback on Product Quality from Internal and External Sources
- Providing Knowledge to Enhance Process Understanding
The ISPE APQ Guide: PPPQMS is the fourth in the series that seeks to improve the state of pharmaceutical quality and ensure sustainable compliance. The Guide Series is part of ISPE’s initiative, Advancing Pharmaceutical Quality (APQ), a comprehensive program for assessing and improving an organization’s quality management maturity.
Parenteral Drug Association (PDA) – Points to Consider
Since health authorities have not yet published guidelines for a comprehensive control strategy specific to microbiological topics for ATMPs, it is up to the individual ATMP sponsor or license holder to apply these compendial references properly. This Points-to-Consider (PtC) document provides a summary of microbiological challenges for ATMPs and guidance on how to address these challenges based on the current state of technology, regulatory environment, and industry best practices. The PtC addresses ATMP process technologies such as cell-free production of mRNA therapeutics, viral vector-induced in-vivo gene therapies, ex-vivo engineering of human cells for autologous, and allogeneic cell therapies. The control aspects covered include facility design, equipment and instrumentation design and maintenance, analyst and operator gowning and qualification, and microbiological process monitoring.
Pharmaceutical Inspection Co-Operation Scheme (PIC/S)
Publication of revised PIC/S Annex 1, 09 September 2022
The Revised Annex 1 to the PIC/S GMP Guide on the manufacture of sterile products has been published and will enter into force on 25 August 2023, except for point 8.123 which is postponed until 25 August 2024. The date of entry into operation is aligned with the revised EU Annex 1, which is identical to PIC/S Annex 1 with some very minor editorial differences. The entry into force closes a long revision process, which has been driven jointly by PIC/S and the EMA GMP/GDP Inspectors Working Group (GMDP IWG) in close co-operation with the European Commission (EC) and the World Health Organization (WHO). This has been a best-in-class model of international co-operation between EC, EMA, WHO, and PIC/S. Annex 1 was first published in 1971 based on a PIC/S recommendation to ensure the sterility of medicinal products for the benefits of patients. It has undergone a number of partial revisions since its publication. This is, however, the first full revision aiming at restructuring this Annex by adding clarity to the requirements on the sterile manufacturing of medicinal products and introducing the principles of Quality Risk Management to allow for the inclusion of new technologies and innovative processes.
Therapeutic Goods Administration (TGA)
The TGA led Australia’s participation in INTERPOL’s Operation Pangea- external site, which tackles the trade of illicit and counterfeit therapeutic goods worldwide, intercepting more than $2 million (USD) of illegally imported products. During a week of action, 94 countries representing every continent cooperated to detect and seize a combined $11 million in illicit and counterfeit therapeutic goods globally. Nearly half of the packages inspected were found to contain illicit or counterfeit medicines and products including anabolic steroids, antibiotics, COVID-19 rapid antigen tests, cosmetic injectables, erectile dysfunction medicines, herbal and sports supplements, ivermectin, nicotine vaping products, pain killers, and sedatives. Over 4,000 websites and web links that advertised and sold these products were also shut down or removed. Dozens of organized crime groups were impacted.
Update to the Manufacturing Principles for medicines, APIs & Sunscreens, 25 August 2022
On 01 July 2022 the TGA adopted the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PE009-15) issued, 01 May 2021, as the Manufacturing Principles for medicines, active pharmaceutical ingredients and sunscreens. The GMP guide is regularly updated and adopted by the TGA to:
- Provide guidance for the management of new technologies
- Address gaps in existing compliance requirements
- Manage risks identified through inspections and regulation
- Facilitate continuous improvements in the way medicines are manufactured
The changes in version 15 relate to Annex 2 – Biological Medicines, which has been split into two sub-annexes:
- Annex 2A: Manufacture of Advanced Therapy Medicinal Products (ATMPs) for Human Use
- Annex 2B: Manufacture of Biological medicinal substances and products for human use’.
Annex 2A contains expanded and additional guidance specific to the manufacture of ATMPs, while Annex 2B remains mostly unchanged from the Annex 2 found in version 14 of the PIC/S guide but with ATMPs excluded from the scope of application. Just as in previous versions of the PIC/S guides, Annexes 2A and B apply to biological medicines including those derived from animal cells and/or tissues. Alternatively, biologicals that comprise, contain, or are derived from human cells and tissues, or are specified as a biological by the TGA, must comply with the Australian code of GMP for human blood and blood components, human tissues and human cellular therapy products.
The adoption of the PIC/S Guide to GMP (PE009-15, 01 May 2021) commenced on 01 July 2022 from which point, GMP inspectors will use the new Guide to GMP during inspections. Compliance with the basic requirements of the PIC/S Guide to GMP (PE009-15, 01 May 2021) is expected from the adoption date.
United States Food and Drug Administration (FDA) – Regulations and guidance
Computer Software Assurance for Production and Quality System Software, 13 September 2022
The FDA is issuing a draft guidance to provide recommendations on computer software assurance for computers and automated data processing systems used as part of medical device production or the quality system. This draft guidance is intended to:
- Describe “computer software assurance” as a risk-based approach to establish confidence in the automation used for production or quality systems and identify where additional rigor may be appropriate.
- Describe various methods and testing activities that may be applied to establish computer software assurance and provide objective evidence to fulfill regulatory requirements, such as computer software validation requirements in 21 CFR Part 820.
When final, this guidance will supplement FDA’s guidance, “General Principles of Software Validation” (“Software Validation guidance”) except this guidance will supersede Section 6 (“Validation of Automated Process Equipment and Quality System Software”) of the Software Validation guidance.
Policy for Device Software Functions and Mobile Medical Applications, 28 September 2022
The FDA is issuing a guidance to communicate how the Agency intends to apply its regulatory oversight to certain software, including device software functions and Mobile Medical Applications (MMAs) intended for use on mobile platforms or on general-purpose computing platforms. The FDA intends to apply its regulatory oversight to those Device Software Functions that meet the definition of a medical device and whose functionality could pose a risk to a patient’s safety if the device were not to function as intended. This guidance describes the FDA’s policy for Device Software Functions and MMAs that meet the device definition, including some that are the focus of the FDA’s regulatory oversight and some for which FDA does not intend to enforce requirements under the Federal Food, Drug, and Cosmetic Act. This guidance also provides information on some software functions that do not meet the device definition and software functions that are not subject to applicable FDA regulatory requirements. The FDA is issuing this guidance to provide clarity and predictability for software manufacturers on this topic.
This guidance provides establishments that manufacture ACTPs meeting the definition of a new animal drug ACTP with recommendations for meeting Current Good Manufacturing Practice (CGMP) requirements. All new animal drugs, including ACTPs, must be manufactured in accordance with CGMPs to ensure that such drugs meet the requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act) regarding safety, and have the identity, strength, quality, and purity characteristics which they purport to or are represented to possess. The FDA recognizes that the manufacture of ACTPs presents unique considerations for complying with regulatory CGMP and that these CGMP regulations do not specifically or fully address all aspects of the manufacture of ACTPs, including initial stages of the ACTP manufacturing process. This document is specific to ACTPs to help establishments that manufacture ACTPs meet statutory and applicable regulatory CGMP. New animal drugs not manufactured in conformity with statutory and regulatory CGMP are adulterated under the relevant provisions of the FD&C Act. In this guidance, FDA addresses the methods, facilities, and controls used for manufacturing ACTPs, including steps in recovery, processing controls, process changes/validation, labeling/packaging, storage, and distribution.
New Inspection Guidance, 26 October 2022
The FDA has updated two Compliance Program Guides (CPGs) on GMP inspections. CPGs are primarily for FDA staff and assist them in evaluating and enforcing regulations for the industry. Many details and interpretations are found there that are not covered by existing FDA laws, regulations, or guidance. CHAPTER 46-New Drug Evaluation deals with Pre-Approval Inspections (PAI) and CHAPTER 56-Drug Quality Assurance with routine surveillance inspections. The revisions to CHAPTERS 46 and 56 add elements of ICH Q9: Quality Risk Management, ICH Q10: Pharmaceutical Quality System, and ICH Q12: Technical Regulatory Considerations for Pharmaceutical Product Lifecycle Management. The revisions also include requirements for control of nitrosamine impurities and alternative tools for evaluating facilities, as noted in Attachment A: Remote Regulatory Assessments.
United States Food and Drug Administration (FDA) – Recalls and Corrections
Eugia US LLC (formerly AuroMedics Pharma LLC) has initiated a voluntary recall of lot number AC22006 of AuroMedics Acyclovir Sodium Injection 500 mg per 10 mL (50 mg/mL), 10 mL single dose vial to the consumer level from the United States market due to a product complaint for the presence of a dark red, brown, and black particulate inside the vial. The administration of an intravenous product containing particulates has the potential to result in inflammation, allergic reactions, or circulatory system complications, which could be life-threatening. To date, Eugia US LLC has not received reports of any adverse events or identifiable safety concerns attributed to the product consumed of this lot.
Exela Pharma Sciences, LLC, (Exela) is voluntarily recalling 49 lots of Sodium Bicarbonate Injection, USP, 8.4%, 50 mEq/50 mL vial, 20-count carton to the consumer level. The product poses a potential safety concern with vial breakage and flying glass when pressurized while preparing the product for administration. Exela has received five (5) reports of flying glass injuring skin, eye and/or other parts. There have been no reports of sterility failures. The product is used for treatment of metabolic acidosis. The recalled lots are labeled with Exela brand (Carton NDC: 51754-5001-5; Vial NDC: 51754-5001-1) and Civica brand (Carton NDC: 72572-740-20; Vial NDC: 72572-740-1). The recall announcement includes the affected Sodium Bicarbonate Injection, USP, 8.4%, 50 mEq/50 mL lots (covering both Exela and Civica brands). All listed lots are supplied in 20-count cartons only. This recall is not expected to cause drug shortage. The product was distributed nationwide to wholesalers, distributors, and other customers between 16 December 2021 and 10 August 2022.
Insulet Corporation announced on 17 October 2022, a Medical Device Correction for all Omnipod DASH Personal Diabetes Managers (PDMs) distributed globally. This action was taken voluntarily with the knowledge of the FDA and other regulatory agencies. Insulet received reports from Omnipod DASH users regarding PDM battery issues, including battery swelling and leakage, and in rare cases, extreme overheating, which has resulted in reports of fire. The Company’s investigation determined that the Omnipod DASH PDM is at increased risk of malfunction if overcharged beyond the maximum battery voltage, which could potentially lead to severe injury or death. There have been 50 complaints about this issue. No serious injuries or deaths have been reported because of this potential issue. As previously communicated to Omnipod DASH users, Insulet has identified an update to the Omnipod DASH PDM that will resolve this issue. The Company expects to begin shipping updated Omnipod DASH PDMs to all current Omnipod DASH customers in the coming months.
United States Food and Drug Administration (FDA) – Warning Letters
Sterling Pharmaceutical Services, LLC Warning Letter, 27 September 2022
The FDA issued a warning letter due to the inspection of the Sterling Pharmaceutical Services, LLC drug manufacturing facility in Dupo, Illinois, which was conducted from 07 February to 18 February 2022. The warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals as specified in 21 CFR Parts 210 and 211. During the inspection, FDA investigators observed specific violations with respect to aseptic processing including, but not limited to, the following:
- The firm identified aseptic processing lines as Restricted Access Barrier Systems (RABS). However, the firm’s systems permitted access to the processing line without the design of rigid wall enclosures. The firm lacked other fundamental elements of a valid RABS design including glove ports which are employed to reduce or eliminate direct operator interventions into the ISO 5 critical area. These glove ports and infrequent door openings provide the foundation for the overall design and control concept of a RABS that reduces the hazard of ingress of contamination from the surrounding aseptic processing cleanroom environment.
- The firm did not adequately investigate excursions above specified Environmental Monitoring (EM) action limits, including an adverse trend of microbiological contamination from the aseptic processing line environment. For example, from 01 January to 31 December 2021, the EM program repeatedly recovered microorganisms from production line ISO 5 areas (air, surface, and personnel) in the facility.
- EM results from 01 January to 16 February 2022, including ISO 5 areas and aseptic processing operator glove samples, showed an adverse trend that revealed compromised environmental control of the aseptic processing operation. The firm continued ophthalmic drug production without adequate investigation and preventive measures to address the persistent microbiological contamination in the ISO 5 environments that posed a risk to product sterility.
- Specific incident investigations into these contamination risks routinely identified poor aseptic behavior by personnel and concluded there was a “very low” risk to drug products. The investigations were inadequate because they did not thoroughly address the persistent adverse trend of microorganisms recovered from ISO 5 areas, including spore-forming bacteria and fungi.
- Environmental monitoring of cleanrooms also recovered gram negative bacterial contamination.
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On 07 July 2021, the firm detected a sterility failure fora lot that was contaminated with Herbaspirillum aquaticum, a gram-negative bacterium. Non-sterile ophthalmic drugs pose unacceptable risks to patients. FDA acknowledged that the firm rejected this lot, however the investigation failed to consider that this sterility failure, in conjunction with the adverse EM trends, may be indicative of contamination risks from the basic design of the processing lines and could impact other batches.
Legacy Pharmaceutical Packaging LLC Warning Letter, 03 October 2022
The FDA issued a warning letter because of the inspection of the drug manufacturing facility for Legacy Pharmaceutical Packaging LLC in Earth City, Missouri from 12 April to 27 April 2022 and identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. The firm repackages and relabels numerous finished drug products intended to treat various conditions. The firm also repackages and relabels controlled substances. Given the scope of drug products that the firm repackages and their intended uses, the prevention of mix-ups is paramount. It was observed that the firm had failed to adequately investigate the presence of foreign tablets in drug products. For example, the firm documented product mix-ups in two separate investigations where a bottle of tablets contained one foreign tablet of an alternate product lot. Both investigations indicated potential equipment design flaws, inappropriate cleaning, and ineffective line clearance. While the firm identified some Corrective and Preventive Actions (CAPAs) to address equipment design and cleaning, the firm did not extend the investigation to determine whether other batches in the same packaging line or within the same facility may also have been impacted. Although the firm identified the existence of non-contemporaneous documentation during their investigation, the firm failed to address records being filled out for work not performed, such as a specified filler cleaning checklist.
Sovereign Pharmaceuticals, LLC Warning Letter, 05 October 2022
The FDA issued a warning letter as a result of the inspection of the drug manufacturing facility for Sovereign Pharmaceuticals, LLC in Fort Worth, Texas from 13 to 22 April 2022. A summary of observations noted is provided below:
- The firm failed to adequately validate the manufacturing processes for bulk tablets. Specifically, during Process Performance Qualification (PPQ) for in-process blend powder drum assay testing, several Out-of-Specification (OOS) results were obtained for at least one of the active ingredients.
- In addition, OOS tablet active ingredient assay and tablet weight results were observed in the validation report. It was also observed that the tablet assay result was outside of the United States Pharmacopeia (USP) Tablet’s monograph acceptance criteria for the specific drug product.
- These multiple OOS results, obtained during PPQ for the firm’s bulktablets also demonstrate a failure to meet the critical quality attributes defined in their protocols and a process that is not in a state of control.
- Additionally, because of the narrow therapeutic range of this product, uniformity is critical; it is especially important to prevent patients with hypothyroidism from receiving insufficient or excessive doses.
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