Drug Product Release Specification Justification

Client lacks knowledge of critical quality standards for drug product release

  • Specifications are critical quality standards that are crucial for approval when submitted to the authorities

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Data Science long-term support to a global submission dossier

Needed to perform multiple calibration studies for IVD

  • Statistical and pharmacokinetic input in each application dossier (e.g. modules 2.7.2 and 5 for FDA)
  • Need to summarize heterogeneous information from different sources and providers used during the clinical development
  • Quick feedback including new analyses to support the answers to the questions raised by the different regulatory agencies

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System suitability control limits for assay with format

Client lacked sufficient knowledge of System Suitability Control (SSC)

  • For assays, scientists develop SSC, to mitigate large assay variability with biologics and vaccine, samples are frequently analyzed in replication over multiple runs, and the mean of all the results is taken as reportable value
  • Variability analysis of these replicates could lead to the detection of assay problem (sample preparation, etc.) but specifications for simultaneous, replicate determinations do not exist to obtain an easy pass / fail decision process

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Post-regulatory support to an EMA clinical submission

Support required to respond to EMA feedback on study results

  • Several concerns raised by EMA on the design of the pivotal study for the registration of a generic drug diffusion system (DDS)

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Validation of SoftMaxPro

Client experienced troubles implementing a protocol validation in SoftMaxPro

  • Definition of the expected results and path were complex
  • Protocol needed to be reworked several times before reaching acceptance

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Development and Implementation of the Robustness Index

Support required to provide success criteria in line with QbD principles

  • Implementation of a Robustness Indexaiming to translate development goals into objectively measurable success criteria to assess scientific knowledge, development and performance data to promote Quality by Design (QbD) principles in manufacturing

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Dilution recipe for vaccine production

Required support to avoid batch rejection due to poor assay performance

  • A vaccine manufacturer produced a bulk drug Substance (DS)
  • Dilution with a formulation buffer is made to obtain a Drug Product ready to be filled in syringes
  • However, the titration of biologic material is subject to large uncertainty due to poor assay performance, leading to frequent and costly batch rejection

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Implementing parallelism tests in JMP

Client was in urgent need for a more cost-effective solution

  • According to (statistical software) USP standards, parallelism between a pair of dose–response functions need to be tested prior to validating a potency bioassay
  • Developing acceptance criteria for one specific assay requires measuring the reference product numerous times
  • These cost a tremendous amount of time and money

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Continuous Manufacturing: Development, Optimization and Validation

Client lacks strategy for Continuous Manufacturing within QbD principles

  • Client lacks experimental strategy to develop, optimize and validate a new continuous Manufacturing (CM) process in Quality by Design (QbD) framework

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Biosimilarity assessment on multiple CQAs

Required multiple CQAs assessment in EU and US

  • How to deal with multiple Critical Quality Attributes (CQAs) in the assessment of a new biosimilar in compliance with EU and US regulations?

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Acceptance criteria for Bioassay validation

Client was in urgent need for a more cost-effective solution for Bioassay validation

  • According to USP standards, parallelism between a pair of dose-response function needs to be tested prior to validating a potency bioassay

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PharmaLex successfully changes legal status of product from POM to P

PharmaLex successfully changes the legal status of the product from POM to P

  • PharmaLex leveraged their regulatory expertise on the switching requirements and process, and their working relationship with the regulatory authorities to successfully change a product from prescription only medicine (POM) to pharmacy medicine status.

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PharmaLex keeps medical device CE marking on track

PharmaLex applies expert knowledge of EU medical device regulation and achieves a positive opinion from the MHRA on a Class III medical device, despite a flawed study design.

  • A US-based company developed a class III medical device with an ancillary medicinal product (according to Rule 13, Annex IX of the Medical Device Directive 93/42/EEC).  The data were positive in a multi-center, randomised, comparative clinical trial but a prospective protocol-defined primary endpoint was flawed and unfortunately this led to early termination of the study.  With the risk of needing to repeat the trial, the company required a partner with specialist knowledge of EU medical device regulations and strong Notified Body experience to avoid a significant delay and costly consequence.

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PharmaLex expertise secures CE certification for medical devices ‘at risk’

PharmaLex expertise secures CE certification for medical devices ‘at risk’

  • An EU based company manufacture a large portfolio of medical devices for the UK National Health Service. During a recent Notified Body audit, the company’s Technical Files were found to be deficient, and they were issued with a major non conformity against their Clinical Evaluation Reports (CERs).
  • With multiple reports requiring update to the new MEDDEV 2.7.1/rev4, there was a real risk of losing their CE certifications and thus, the right to sell their products in the EU. This manufacturer required a consultancy specializing in medical devices, who had clinical writing expertise and strong literature retrieval skills, together with the commitment and can do attitude to meet a very tight deadline.

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PharmaLex delivers huge sales upturn with regulatory strategy

PharmaLex ensures regulatory compliance for successful pharmaceutical product acquisition with sales growth of 22% in the first year

  • A pharmaceutical company had an opportunity to buy their first medicine and needed to understand their pharmaceutical regulatory compliance obligations prior to acquisition. This was a product that had been sold for a number ofyears in many countries across the world, so there was a huge amount of complex technical and scientific data. The medicine was used to treat potentially life-threatening infections and therefore played a vital role in critical care.

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PharmaLex corrects serious non-compliance issue

PharmaLex corrects serious non-compliance issue and protects millions of £s of annual sales for product range

  • PharmaLex were given the responsibility of providing regulatory services to a pharmaceutical company who had acquired two licensed medicines in a range of formulations and strengths from big pharma. These originator products had EU sales in the millions and PharmaLex were engaged to provide regulatory support to all the client’s local EU affiliate offices.

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PharmaLex obtains rapid CE marking

PharmaLex obtains rapid CE marking for a medical device that opens up a market worth $2.2 billion

  • A US-based company had developed a Class III medical device for the treatment of hepatic cancer. The device had been designed to be used with a specific medicinal product. The company wanted to sell their product in the EU and the product must therefore carry a CE mark.

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PharmaLex applies EU regulatory affairs expertise

PharmaLex applies EU regulatory affairs expertise to rescue failing market application and delivers €3m revenue in first year sales

  • A pharmaceutical company had submitted a marketing application for a new product seeking approval in ten EU countries. The company required a partner with specialist EU regulatory affairs knowledge to avoid a costly failed application.

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Portfolio Maintenance Outsourcing Local RA responsibility – EU

Client plans to outsource RA activities in EU countries for defined products

  • High workload in local affiliates for established product portfolio in the EU
  • New products registered in the countries lead to increasing workload
  • Full RA responsibility for an established product portfolio to be outsourced for 16 EU countries
  • Cover of all RA life cycle management tasks including labeling and interaction with local partners (incl. PV, medical)
  • HA interactions done directly by PharmaLex

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Parallel NDA/MAA eCTD Submission

3 dossiers  (an NDA and 2 MAA) for initial application for DP for prevention of pregnancy

  • Dossiers for EMA and FDA with differences in the requirements
  • Support for the client (one US NDA and one EU MAA) and their third-party collaboration partner (one additional EU MAA)
  • Differences in the administrative part of the dossiers and following updates of M1 and M2 documents
  • Short notice changes before the planned submission dates due to difficult alignment between affected parties

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Regulatory Operations IND transition to eCTD

PharmaLex network of resources and experience utilized to guide the client to success

  • CMC subject matter expertise for gene therapy was provided to effectively map eCTD locations of legacy documents
  • Anchor eCTD submissions were established and dispatched through the FDA electronic submissions gateway to begin the eCTD submission management
  • Experienced regulatory operations managers guided the client regarding the nature of lifecycle operators and eCTD granularity
  • Technical support was provided for eCTD templates

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MA applications to EMA and FDA in parallel

  • A European pharmaceutical company has identified the need for support from a service provider due to the lack of capacities and capabilities to process both applications in parallel
  • Support for various regulatory activities in relation to the preparation, submission and coordination of both applications (EU/US)
  • Outstanding Project Management expertise required to meet requirements of large project

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Dendritic cell vaccine (oncology)

  • Small biotech US company developing a dendritic cell vaccine for the treatment of the Orphan indication glioblastoma in EU
  • Timeline: long-term (8 years)
  • Support in

-Preparation and conduct of the Scientific Advices (SA)

-Medical and technical Writing

-Clinical trial Phase III

-Adaptive pathway

-Early access medicines scheme (UK)

-Hospital exemption (DE)

-Pediatric Investigational Plan (PIP)

-Pharmacovigilance: DSUR and PSUR

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Regulatory CMC Compliance reduced risk

  • Identified deficiencies in Change Control procedures and GMP manufacturing documentation
  • Uncertainty in verifying the current registered information held with Health Authorities
  • Lack of Regulatory Information Management (RIM) systems and therefore lack of oversight of product information for key stakeholders

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Definition of batches internal release limits based on stability results

A client faces multiple batch rejection due to outdated Internal Release Limits (IRLs) but he has 100+ products (500+ attributes) to analyze and follow up on a regular basis

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Pre-IND Meeting

  • Company beginning first discussions with the FDA regarding IND development and submission of intra-cerebral gene therapy product
  • Intent to gain agreement on completed nonclinical program to support first in human study
  • Intent to gain agreement on the use of historical controls to support clinical development in rare disease space

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Type C Meeting

US Company developing a patient-reported outcome (PRO) as the primary endpoint for the Phase 3 program

  • Under guidance from FDA, the company performed multiple Phase 1 and 2 studies to support validation of PRO efficacy measuring tool
  • Company intent to gain agreement on validation of PRO for use in Phase 3 studies to support small molecule development for celiac disease

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RIM-DMS Data Clean-up

300 GB of unstructured and partially structured documents, and files during marketing authorization transfer

  • The client acquired a large portfolio of marketing authorizations
  • Data transfer was documented, but documents and files were highly unstructured
  • Fully structured and valid data, documents and files to be imported into Veeva Vault RIM
  • Timelines for the project defined by marketing authorization transfer submissions and any regulatory maintenance activities

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Consultancy and eCTD submission support for master files

Manufacturer with limited eCTD knowledge and several Holder’s sites in the EU, US and China

  • Client needs to switch Master Files (MF) to eCTD format in EU, non-EU and US (later also APAC, CA)
  • Pressure from their clients (MAHs) to use eCTD
  • PharmaLex supported with:
    • Knowledge transfer, Project planning + management
    • Gap analysis and roadmap for transition
    • Full Regulatory Operations services during transition and on-going maintenance of eCTD-MFs (eCTD-readiness, compile, publish, submit)
    • Consultancy on CMC and (pre-)publishing topics and tools

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Consultancy and support for IDMP implementation

  • Medium-sized pharmaceutical company in the EU
  • Client intends to prepare for upcoming IDMP implementation in Europe
  • Focus on compliance and optimal utilization of related information within the company
  • PharmaLex supported with:
    • Awareness meetings
    • Gap analysis
    • Implementation proposal covering systems, processes and data

 

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Global CMC responsibility during portfolio integration

Tight contractual agreed timeframe and multiple data migrations and process adaptations

  • Portfolio acquired by client for which CMC maintenance already handled by PharmaLex >8 years before acquisition.
  • PharmaLex with same functional role in new company but different scope of work.
  • Compliance with changing client processes due to data migration.
  • Portfolio with > 80 INNs (chemicals, herbals, biologics) authorized worldwide.

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Regulatory CMC compliance reduced workload by 20-25%

High additional workload due to expansion in product portfolio

  • More than 150 different formulations, resulting in more than 1200 national registration documentations worldwide.

 

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Flexible eCTD publishing support

Global innovator company looking for flexible support and ability to meet tight deadlines

  • Global innovator company and European generics arm requiring UK local affiliate support.
  • Covering MAAs and post-approval submissions.
  • More than 250 MAs
  • Typically 25 – 30 eCTD sequences required per week across the portfolio.

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eCTD submissions for global DMF portfolio

Client was lacking internal expertise during workload peaks

  • Big multi-national chemical company.
  • Client intended to switch all existing Drug Master Files (DMF – active substances as well as excipients) into eCTD format.
  • Portfolio also included Veterinary Master Files, which require a specific electronic submission format.

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Regulatory publishing support on request

Client lacking resources for EU publishing activities

  • Global generic company needed support for EU publishing activities for parts of its product portfolio.
  • All EU eSubmission activities (eCTD, NeeS) were transferred to PharmaLex.
  • Scope of PharmaLex responsibilities:
    • Direct correspondence and interactions with Regulatory Affairs functions.
    • Collection of related documentation.
    • All dossier as well as submission activities.

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Due diligence for medicinal product documentation

Evaluation of drug product documentation under time pressure

  • Medium-sized EU-based pharmaceutical company.
  • The client intended to acquire the marketing authorizations for three strengths of an oral anti-diabetic medicinal product intended for use in patients with type II diabetes.
  • Client was in the need of due diligence to review the dossier and assess the quality of a planned acquisition by the company before imminent expiry (Sunset Clause).

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Preparation, submission and coordination of a CP for PUMA

Needed expertise for regulatory strategy and support for execution for CP and PUMA formulation

  • A small European pharmaceutical company has identified the need for support due to lack of capacity and capability to process a centralized procedure for a PUMA formulation.
  • PharmaLex offered support for various regulatory activities in relation to the preparation, submission and coordination of the centralized procedure.
  • Project management.
  • Definition and tracking of KPIs and budget.

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