Pharma GMP News of the Week Oct 18, 2023

Pharma GMP News of the Week: 18-Oct-2023

Period: May 21, 2023 to Jul 31, 2023

FDA published guideline on “Generally Accepted Scientific Knowledge in Applications for Drug and Biological Products: Nonclinical Information”

Date: May 24, 2023

FDA has received an increasing number of questions regarding the extent to which generally accepted scientific knowledge (GASK) may be relied on for drug or biological product approval. This guidance describes instances in which it may be appropriate to rely on GASK to meet certain nonclinical safety requirements for new drug applications (NDAs) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) and biologics license applications (BLAs) under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262(a)).  The information that supports the nonclinical safety of a drug and that must be submitted in the application can include references to GASK, when appropriate, instead of or in addition to, specific studies conducted with respect to the drug.  In such cases, therefore, it might be unnecessary to conduct certain nonclinical studies.


FDA published guideline on “Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products”

Date: May 26, 2023

This guidance describes FDA’s current recommendations regarding adjusting for covariates in the statistical analysis of randomized clinical trials in drug development programs. This guidance provides recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. The main focus of the guidance is on the use of prognostic baseline covariates to improve statistical efficiency for estimating and testing treatment effects. This guidance does not address use of covariates to control for confounding variables in non-randomized trials, the use of covariates in models to account for missing outcome data (National Research Council 2010), the use of covariate adjustment for analyzing longitudinal repeated measures data, the use of Bayesian methods for covariate adjustment, or the use of machine learning methods for covariate adjustment.


FDA published guideline on “Migraine: Developing Drugs for Preventive Treatment”

Date: May 26, 2023

The purpose of this guidance is to assist sponsors in the clinical development of drugs for the preventive treatment of migraine. Pharmacological approaches to the treatment of migraine include drugs to abort migraine attacks as they arise (acute treatment of migraine) and drugs to reduce the frequency of migraine attacks (preventive treatment). Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall development program and clinical trial designs to support approval of drugs for the preventive treatment of migraine. This guidance does not address the development of drugs indicated for the acute treatment of migraine. Such development has been addressed in the guidance for industry Migraine: Developing Drugs for Acute Treatment (February 2018).


 MHRA has published blog on its website on ICH E6 (R3) Good Clinical Practice

Date: May 26, 2023


FDA published guideline on “Cover Letter Attachments for Controlled Correspondences and ANDA Submissions”

Date: June 05, 2023

This guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence2 to the Office of Generic Drugs (OGD), as well as original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA. These attachments do not replace the recommendations for the content of cover letters provided in other FDA guidances.


FDA published guideline on “Nonclinical Evaluation of the Immunotoxic Potential of Pharmaceuticals”

Date: June 05, 2023

 The purpose of this guidance is to assist sponsors in the nonclinical evaluation of the immunotoxic potential of pharmaceuticals. Immunotoxicity is, for the purposes of this guidance, defined as unintended immunosuppression or stimulation (including hypersensitivity), which can include adverse effects of exaggerated pharmacology of pharmaceuticals that are intended to act as immunomodulators. This guidance applies to drug products, including small molecule drugs and oligonucleotides, as well as certain biological products such as biotechnology-derived therapeutic proteins (referred to herein as biopharmaceuticals). For the purposes of this guidance, the term pharmaceutical will be used as a general term that encompasses all of these product types. Cell and gene therapies, adjuvanted vaccines, and blood products are not within the scope of this guidance.


FDA published guideline on its website “E6(R3) GOOD CLINICAL PRACTICE (GCP)”

Date: June 06, 2023

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “E6(R3) Guideline for Good Clinical Practice.”  The draft guidance was prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).  The draft guidance outlines modernized Good Clinical Practice considerations to guide thoughtful design and responsible conduct of clinical trials in a manner that ensures participant safety and the reliability of trial results.  This draft guidance encourages innovation, focuses on quality, and establishes proportionate and risk-based approaches for conducting clinical trials, while minimizing unnecessary complexities.  The draft guidance is intended to provide flexible, modern, and clear Good Clinical Practice for conducting clinical trials


News from EDQM “EDQM publishes 2nd edition of Herbal Guide”

Date: June 07, 2023

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has just published a new edition of the Guide for the elaboration of monographs on herbal drugs and herbal drug preparations. This guide is invaluable for the authors of monographs on these substances, and also helps users of the European Pharmacopoeia (Ph. Eur.) to understand the principles behind the drafting and revision of herbal monographs.

 This 2nd edition of the Guide, as approved by the Ph. Eur. Commission at its 175th session, has been completely overhauled and updated to reflect the latest versions of the relevant monographs and to take account of new Ph. Eur. texts published since the first edition was issued in 2005. For example, the sections on ‘Assay’ and ‘Herbal drug preparations’ have been substantially revised and expanded and the guide also includes new and useful information such as an example schematic drawing of the characteristic microscopic features of a powdered herbal drug and a section on identification by HPTLC (in accordance with general chapter 2.8.25. High-performance thin-layer chromatography of herbal drugs and herbal drug preparations). A new section referring to the recently implemented general chapter 2.8.26. Contaminant pyrrolizidine alkaloids – compounds found naturally in many common weeds that may adulterate herbal drugs – has also been added.

The Guide, together with other Ph. Eur. technical guides, is available on a dedicated page of the EDQM website.


FDA published guideline on its website “Assessing User Fees Under the Generic Drug User Fee Amendments of 2022”

Date: June 09, 2023

This guidance provides information to stakeholders regarding FDA’s implementation of the Generic Drug User Fee Amendments of 2022 (GDUFA III) under Title III of the FDA User Fee Reauthorization Act of 2022. Because GDUFA III created changes to the user fee structure, this guidance serves to provide an explanation about the new fee structure and types of fees for which entities are responsible.

This guidance describes the types of user fees authorized by GDUFA III, and the processes for submitting payments to FDA, the consequences for failing to pay generic drug user fees, and the process for requesting a reconsideration of a user fee assessment previously developed under earlier GDUFA authorizations.  This guidance also describes how FDA determines affiliation for purposes of assessing generic drug user fees.  FDA will issue separate guidance documents regarding GDUFA III non-user fee requirements and processes.  This guidance does not address how FDA determines and adjusts fees for each fiscal year, nor does it address FDA’s implementation of other user fee programs (e.g., under the Prescription Drug User Fee Act (PDUFA) or Biosimilar User Fee Act (BsUFA)).  Throughout this guidance, references to user fees or the user fee program indicate generic drug user fees assessed and collected under section 744B of the Federal Food, Drug, and Cosmetic Act (the FD&C Act).


News from EDQM “Revised Policy document PA/PH/CEP (04) 1, 7R on Content of the CEP dossier released for public consultation”

Date: June 19, 2023

The European Directorate for the Quality of Medicines & HealthCare (EDQM) is revising the policy document PA/PH/CEP (04) 1, 6R ‘Content of the dossier for CEP applications for chemical purity and microbiological quality of substances for pharmaceutical use’.

The draft document for public consultation is now available in the consultation space. The consultation deadline for this document is 15 September 2023. After the consultation phase the final policy document will be made available on the EDQM website.


EMA publishes review of its studies on “Use of real-world evidence in regulatory decision making”

Date: June 23, 2023

Real-world evidence (RWE) from studies led by regulators can complement evidence from other sources including clinical trials. RWE can support both pre-authorisation and post-approval assessments of EMA’s scientific committees, working parties and national competent authorities. However, more effort is needed to better anticipate the need for such studies and to speed up their initiation to ensure that regulators have access to RWE in a timely manner.


News from EDQM “European Pharmacopoeia Supplement 11.3 now available”

Date: July 01, 2023

The European Pharmacopoeia (Ph. Eur.) Supplement 11.3 is now available and will be applicable in 39 European countries as of 1 January 2024.

This volume is included in the 2024 subscription (11.3, 11.4 and 11.5) to the 11th Edition of the Ph. Eur. Subscriptions for print and/or electronic versions are already available to purchase via the EDQM Store.


News from EDQM “Pharmeuropa 35.3 just released”

Date: July 03, 2023

All new European Pharmacopoeia (Ph. Eur.) texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation. The deadline for comments on Pharmeuropa 35.3 is 30 September 2023.

Users and interested parties are welcome to comment on these drafts. It should be noted that:

 Although draft monographs must not be regarded as official standards, they will, once adopted by the Ph. Eur. Commission at a later date, become applicable and legally binding standards for the products concerned in all Ph. Eur. member states; if general texts are not legally binding per se, they become mandatory when referred to in a monograph. Changes to general texts may therefore impact monographs.

It is therefore extremely important that users provide feedback on such drafts.

 Comments made after adoption of the text and/or publication in the Ph. Eur. will be too late to be considered. Users may then be in a position where their product is not compliant with the Ph. Eur. monograph, which is a legal standard in Europe. This could ultimately lead to a situation where a product can no longer be marketed in Europe.


News from PIC/S “Publication of revised PIC/S GMP Guide (PE 009-17)”

Date: July 2023

PIC/S has published the revised PIC/S GMP Guide (PE 009-17), which includes the revised Annex 1 (for the background to the revision. PE 009-17 will enter into force on 25 August 2023. In the meantime, the current version of the PIC/S GMP Guide (PE 009-16) remains in force. Both versions of the PIC/S GMP Guide are published on


EMA Begins to Phase Out COVID-19 Regulatory Flexibilities

Date: July 06, 2023

The European Medicines Agency (EMA) has started to phase out the regulatory flexibilities introduced during the COVID-19 pandemic. These flexibilities, which included aspects such as marketing authorization, manufacturing, imports, quality variations, labeling, packaging and compliance, were implemented to mitigate the pandemic’s impact on the pharma industry. With the World Health Organization declaring an end to the COVID-19 public health emergency, EMA has begun to gradually phase out these measures. However, certain allowances, such as English-only labeling of COVID-19 vaccines and extended validity of good manufacturing and distribution practice certificates, will continue until the end of the year to minimize disruption.


The National Pharmaceutical Regulatory Agency (NPRA) of Malaysia has issued a guideline to regulate nitrosamine impurities in pharmaceutical products.

Date: July 07, 2023

This guideline allows product registration holders to submit their compliance documents, originally created for European and US requirements, to meet NPRA’s standards.

The guideline is applicable to all chemically synthesized active pharmaceutical ingredients (APIs) in pharmaceutical products intended for human use. However, it excludes non-scheduled poison, natural, and health supplement products. The guideline’s scope may be extended to include any products found to have nitrosamine impurity issues.

In formulating this guideline, NPRA has taken into account the guidance provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).


FDA’s Digital Transition for Medical Device Export Documents

Date: July 10, 2023

From 2nd January 2024, the US Food and Drug Administration (FDA) will digitize key export documents for medical devices to enhance efficiency and reduce environmental impact. The documents will be available as downloadable PDFs from the Center for Devices and Radiological Health’s (CDRH) Export Certification Application and Tracking System (CECATS). They can be validated via the FDA Unified Registration and Listing Systems (FURLS) Export Certificate Validator (FECV) database. Paper certificates will only be issued for requests received by 15th December 2023, and those reviewed before 2nd January 2024. Post this date, all requests will be processed electronically.


EMA’s Lifecycle Approach to AI/ML Drug Development

Date: July 13, 2023

The European Medicines Agency (EMA) has published a draft reflection paper detailing its approach to the use of artificial intelligence/machine learning (AI/ML) in drug development. The paper, developed by EMA’s Big Data Steering Group and the Heads of Medicines Agencies, outlines the use of AI/ML throughout the lifecycle of drugs, including during product development, authorization, and post-authorization.

The paper emphasizes that AI/ML tools can potentially support the acquisition, transformation, analysis, and interpretation of data across the medical product’s lifecycle. For instance, AI/ML modelling could be used to replace animal models during preclinical development. In clinical trials, AI/ML systems could support patient selection based on disease characteristics or other clinical parameters.

At the marketing-authorization stage, AI applications could be used to draft, compile, translate, or review data to be included in the product information of a medicine. In the post-authorization phase, such tools can support pharmacovigilance activities including adverse event report management and signal detection.

However, the use of AI/ML also brings challenges such as understanding the algorithms, their design and possible biases, as well as the risks of technical failures and their wider impact on AI uptake in medicine development and health.


FDA Drafts Guidance on Determining Non-Compliance with Postmarketing Requirements

 The US Food and Drug Administration (FDA) has issued a draft guidance outlining how it determines if an applicant has shown good cause for failing to meet postmarketing requirements (PMRs) for human prescription drugs. The guidance applies to prescription drugs under section 505 and does not include non-prescription drugs, pediatric studies, accelerated approval trials, or trials required based on evidence from animal studies. Instances of non-compliance include missed milestones for final protocol, study completion, or final report submission. The FDA encourages proactive communication from applicants about progress and potential delays. Enforcement actions for non-compliance can include warning letters, misbranding charges, and civil monetary penalties.


Singapore’s HSA Drafts Legislation on Active Pharmaceutical Ingredient Regulation

Date: Jul 17, 2023

Singapore’s Health Sciences Authority (HSA) has released draft legislation for regulating active pharmaceutical ingredients (APIs), aiming to establish a risk-based licensing framework in line with international standards. The proposed law will apply to APIs used in the manufacture of therapeutics, cell tissue or gene therapies, and medical devices. The HSA plans to implement inspection and licensing controls for all manufacturers, importers, and wholesalers of APIs used in health products for local clinical use. The authority is seeking feedback on these proposals until 17th August. Concurrently, HSA is also seeking feedback on the lead times companies will need to prepare for full implementation of the submission requirement for evidence of Good Manufacturing Practice (GMP) compliance for chemical drug substance manufacturers.


WHO Proposes Best Practices for Clinical Trials

Date: July 19, 2023

The World Health Organization (WHO) has issued a draft guidance outlining scientific and ethical considerations for well-designed clinical trials. The guidance aims to strengthen the clinical trial ecosystem and improve the enrollment of under-represented populations.

The document emphasizes that good clinical trials should be designed to produce scientifically sound answers to relevant questions, respect the rights and well-being of participants, and have processes proportionate to their context and associated risks. It also addresses the issue of over interpretation of existing regulations and guidance for clinical trials, which has led to excessive bureaucracy and unnecessarily onerous procedures.

The guidance suggests efforts need to be made to recruit diverse populations into clinical trials. The research community is encouraged to engage with patients, the public, and communities to include as broad and varied a population as possible.

The document complements existing ethical and scientific standards in conducting clinical trials with a focus on under-represented populations. It does not supersede any existing guidance.


WHO’s Proposed Alignment with Global Bioequivalence Classifications with ICH

Month: July 2023

The World Health Organization (WHO) is proposing to align its bioequivalence classifications with global guidelines, reducing the need for in vivo studies to prove bioequivalence with a reference product. The draft document, Biopharmaceutics Classification System-Based Biowaivers, would align WHO’s policies with those adopted by the International Council for Harmonisation’s 2019 M9 Biopharmaceutical Classification System-Based Biowaivers guideline.

The proposal allows an active pharmaceutical ingredient (API) to be considered bioequivalent if it exhibits the same properties of aqueous solubility and intestinal permeability in lab studies. WHO categorizes APIs into four classes, with biowaivers only available for Class I and Class III APIs.

The document details how to assess solubility and permeability of APIs. An API is considered highly soluble if the highest single therapeutic dose is completely soluble in 250 mL or less of aqueous media over the pH range of 1.2–6.8 at near body temperature. An API is considered highly permeable if the absolute bioavailability is at least 85%, or if 85% of the administered dose can be recovered in urine as parent drug.

A Finished Pharmaceutical Product (FPP) might also be eligible for a biowaiver if all of its APIs satisfy the solubility and permeability requirements of being Class I or III agents; if the FPP is an immediate-release oral medication; and if it is the same dosage form and strength as the reference product. BCS-based biowaivers can only be applied to immediate-release, solid, oral forms or suspensions that deliver the API directly to systemic circulation.

Excipients in a formula can affect a product’s potential qualification for a BCS-based biowaiver. They can impact solubility, gastrointestinal motility, transit time, intestinal permeability and systemic absorption. To qualify for a BCS-biowaiver, the total amount of excipient has to be within a 10% range of the reference product’s excipient.

The European Medicines Agency (EMA) has provided further guidance on remote batch certification and residency requirements for qualified persons.

Month: July 2023

In their updated Q&A, the EMA clarified that remote batch certification might be permissible, provided it is allowed by the national regulator of the location where the authorized site is based. Manufacturers are advised to comply with local regulations. The EMA also highlighted several considerations for manufacturers, including the provision of necessary equipment at facilities to facilitate remote certification, and discussed the technical prerequisites.

Furthermore, the EMA clarified that there are no EU-wide rules regarding the residency of qualified persons. However, they noted that local regulations may apply in certain member states.


FDA Recognizes New Medical Device Sterilization Standards

Date: Jul 24, 2023

The Food and Drug Administration (FDA) has recognized a new international consensus standard, ISO 22441:2022, on the use of low temperature vaporized hydrogen peroxide for sterilizing medical devices. This comes amid efforts by the US Environmental Protection Agency (EPA) to limit the use of ethylene oxide (EtO), a commonly used sterilant.

The standard offers an alternative sterilization method to device makers. The FDA also recognized two standards from AAMI related to technical information reports on medical device sterilization, aimed at advancing sterilization methods and assisting manufacturers in making changes to radiation sterilization processes.

The FDA’s recognition of these standards means they are deemed acceptable, and manufacturers can declare conformity to these standards to meet premarket submission or other requirements. This move supports supply chain resiliency.

However, concerns have been raised about the potential impact of restrictions on EtO sterilization on medical device supply constraints and shortages. In response, the FDA has been working on developing alternatives to EtO for medical device sterilization and launched a voluntary Radiation Sterilization Master File Pilot Program.


Australia’s TGA Proposes New Medical Device Application Audit Framework

Date: Jul 24, 2023

Australia’s Therapeutic Goods Administration (TGA) is seeking feedback on a proposed framework for auditing medical device applications. The proposal comes in response to changing EU regulations, industry concerns, and other factors.

The TGA assesses all applications against regulatory requirements, but some submissions are selected for a more thorough assessment known as an audit. The TGA has operated under interim processes for reviewing European Union Medical Device and In Vitro Diagnostic Regulation (MDR/IVDR) applications since July 2021.

The proposed new application audit framework is designed to be more responsive and risk-based. The TGA will select applications for audit based on postmarket signals, regulatory reforms, and regulatory intelligence. The aim is to provide more predictability and transparency regarding the types of applications likely to be selected for audit.

The TGA is also proposing to explore pathways for Class III devices supported by the Medical Device Single Audit Program (MDSAP) and US Food and Drug Administration (FDA) 510(k) clearance. Feedback is being sought on whether it would be worthwhile establishing a pathway for Class III medical devices based on MDSAP certification and US FDA 510(k) approval.

The TGA is accepting feedback on the draft until 4 September.


The Food and Drug Administration (FDA) has announced the availability of a final guidance for industry titled “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” and two supplemental documents titled “M7(R2) Addendum: Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes” and “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Questions and Answers”.

Date: Jul 25, 2023

These documents were prepared under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). They aim to harmonize the considerations for assessment and control of DNA reactive (mutagenic) impurities. This is an important step in ensuring the safety and efficacy of pharmaceuticals. The guidance and supplemental documents provide valuable information for industry professionals involved in the development and manufacturing of pharmaceuticals. They offer a comprehensive approach to limit potential carcinogenic risk from DNA reactive (mutagenic) impurities.


FDA Finalizes Guidance on Drug Quality Consensus Standards Recognition Program

Date : Jul 26, 2023

The US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has published a final guidance on its process for recognizing voluntary consensus standards (VCS) related to pharmaceutical quality. The aim is to promote innovation in pharmaceutical development and manufacturing, and streamline the preparation and assessment of marketing applications.

The program applies to a range of CDER-regulated products, including brand drugs, generics, biologics, biosimilars, and over-the-counter medicines. The guidance describes CDER’s plans to publish a comprehensive listing of recognized voluntary consensus standards related to pharmaceutical quality and outlines CDER’s policies and procedures for recognizing such standards.

The use of a recognized standard remains strictly voluntary. The program does not apply to regulatory requirements, such as certain provisions of the Federal Food, Drug, and Cosmetic Act relating to the United States Pharmacopeia. The program does not include electronic data exchange standards.

The final guidance includes a new section on requesting recognition in submissions and communicating with requestors. It also details how staff and stakeholders can submit a recognition request electronically through the CDER Direct nextGen Collaboration portal. Additionally, it includes a new section on how CDER’s Pharmaceutical Quality Standards Working Group will update CDER’s standards database.


FDA Completes First Joint Assessment with EMA in ICMRA Pilot

Date: Jul 28, 2023

The US Food and Drug Administration (FDA) has announced the completion of its first collaborative assessment of a post-approval change for an oncology medicine with the European Medicines Agency (EMA). This was conducted under the International Coalition of Medicines Regulatory Authorities’ (ICMRA) joint review pilot program.

The joint assessment teams had a positive and productive experience, producing a common set of highly aligned information requests and comments to the applicant. The assessment resulted in an FDA approval without any delay in the standard assessment timeline. In fact, it was completed under the four-month goal window for a standard manufacturing supplement assessment.

The EU approved the submission on the same day as the FDA. The joint assessment received positive feedback from industry. The ICMRA has accepted several proposals for the postapproval assessment pilot, including this recently completed FDA/EMA supplement assessment.

The ICMRA is also running a hybrid inspection pilot, which has accepted two proposals. For both proposals, regulators will conduct a collaborative facility assessment using a combination of on-site inspection and remote assessment tools. These pilots are due to be completed by early 2024.


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