E&L Problem

WHY DO WE HAVE TO TEST?


🌐 Quality by Design Inc. - Your Trusted Partner in E&L Studies 🌐

At Quality by Design Inc., we pride ourselves on being at the forefront of the Extractables and Leachables (E&L) study landscape. Our comprehensive services cover:


🔍 Consultation on the current E&L study approach 

🔬 Critical assessment and evaluation 

📜 Extractables & Leachables study and profiling 

🧪 Identification & Toxicological evaluations 

🛡️ Risk and Safety assessments 

✅ Regulatory Registration support


Key Areas of Expertise:

  • Container closure systems like glass vials, stoppers, prefilled syringe, patch, medical and related products.
  • Single-use systems and process contact materials such as tubing, bag, filter
  • Steril grade filter related Leachables and Extractables refer to EU GMP Annex 1
  • All types of Medical Devices.

"We proudly showcase our global regulatory expertise, with a track record of obtaining product approvals across:

  • FDA, EMA, CHINA, KOREA, JAPAN, BRASIL, Türkiye(Turkey) and more.

Have an inquiry or need expert advice? 📩 Reach out to us at qbd@qbd.co.kr

For a more in-depth look at what we offer, visit our official website at www.qbd.co.kr

Let's navigate the complexities of E&L together! We look forward to partnering with you. 💼🌟


E&L and Pharmaceutical Regulatory Compliance AI


의약품 인허가 관련 질문하시고 간단한 답변 받으실 수 있습니다.



Beta test 중입니다. 회원가입 후 체험해 보실 수 있습니다.



E&L Study overview


USP General Chapter Updates:  


USP <1663> and <1664>

– Conducted a survey to identify stakeholder needs (Apr 2024)

– Intended to receive inputs and revise chapters

– Total 190 respondents  


New Chapter Proposals:

– To address special considerations for Leachable assessment in various drug products

– USP Subcommittee is currently working on 

• <1664.2> Leachable Chapter for Parenteral Drug Products [Tentative Timeline: FY 25 Q2] 

• <1664.3> Leachable Chapter for Ophthalmic Drug Products [Tentative Timeline: FY 25 Q3] 

• <1664.4> Leachable Chapter for Topical and Transdermal Drug Products [Tentative Timeline: FY 25 Q4] 

• <1664.5> Leachable Chapter for Oral Dosage forms [Tentative Timeline: FY 25 Q3]


Existing chapters to support E&Ls:

– <1663> Assessment of extractables associated with pharmaceutical packaging / delivery systems.

– <1664> Assessment of drug product leachables associated with pharmaceutical packaging / delivery systems.

– <1665> Characterization and qualification of plastic components and systems used to manufacture pharmaceutical drug products and biopharmaceutical drug substances and products

– <1664.1> Orally inhaled and nasal drug products (OINDPs).

– <381> Elastomeric components in injectable pharmaceutical product packaging / delivery systems

– Others (<87>, <88>, <665>, <661.1>, <661.2>, etc.,)



Safety = E&L Study 


E&L Study 의 목적은 의약품 포장이 안전하고 의약품에 부정적인 영향을 미치지 않는다는 것을 보증하는 것입니다. 이러한 맥락에서 inhaler 와 prefilled syringe 와 같은 의료기기도 1차 포장 시스템 (container closure system) 으로 간주됩니다.


추출물 (Extractables) : 추출물 연구를 위한 추출 시험조건에서, 추출용매로 추출될 수 있는 포장 및 전달시스템, 포장 구성요소(packaging component) 또는 포장 구성 재료(packing materials of construction) 에서 추출되는 유기 또는 무기 화학물질


 침출물 (Leachables) : 일반적인 저장 및 사용조건 또는 가속 안정성 시험 동안 용기 마개 시스템에서 “제형(formulation)” 으로 침출되는 유기 및 무기 화합물


- 침출물(leachables)은 환자에게 바로 투여될 수 있는 유기 또는 무기 화학물질입니다.

Key Referance for DS and DP container closure system


PQRI / USP 1663USP 1664 / ISO 10993 part 1 / ISO 10993 part 12 / ISO 10993 part 18 / ICH Q3E(comming soon, 2025)


Key Referance for Process contact materials for DS manufacturing process and DP manufacturing process 

          USP665 (year 2026) / USP1665 / BPOG /  ISO 10993 part 1 / ISO 10993 part 12 / ISO 10993 part 18


EU GMP Annex 1 : Single use system / Sterile grade filter :: Leachables study 



Other special topic related container closure system

         CCIT (Container closure integrity testing : Dye, Microbial ingress, O2 Head space) / Glass delamination / Silicone oil / Tungsten / Nitrosamine / Teflon / Particulate matter / Elemental impurity.  


 


〈1664〉 ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS


Leachables are foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies. Because leachables are derived from the packaging or delivery system, they are not related to either the drug product itself or its vehicle and ingredients. Leachables are present in a packaged drug product because of the direct action of the drug product on the source of the leachable.


Thus leachables are typically derived from primary and secondary packaging, because the primary and secondary packaging can serve as a barrier between the packaged drug product and other potential sources of foreign chemical entities (e.g., tertiary packaging and ancillary components). In certain circumstances, packaging may directly contact the patient under typical clinical conditions of use (e.g., the mouthpiece of a metered dose inhaler). As a result of this contact, patients may be exposed to leachables from the packaging without the action of the drug product. Leachables are typically a subset of extractables or are derived from extractables. Note that chemical entities can also migrate from packaging/delivery systems to patients via direct contact.  [Lechables와 같은 화학 물질들은 포장/전달 시스템에서 환자로 직접 접촉을 통해 이동할 수 있음.]


부연설명: 

침출물(Leachables)은 drug product의 포장 또는 전달 시스템으로부터 formulation으로 이동하는 다양한 화학 물질을 지칭합니다. 이러한 침출물은 포장 소재나 구성 요소의 화학적 반응으로 인해 formulation으로 이동할 수 있습니다. 침출물은 대부분 포장 또는 전달 시스템의 직접적인 영향 아래에서 발생하며, 이러한 물질들은 사용자나 환자에게 원치 않는 노출을 초래할 수 있습니다. 특히 포장이 환자와 직접 접촉하는 경우에는, 침출물로 인한 노출 위험이 더욱 증가합니다.


USP<1664>의 정의에 따르면, 침출물은 포장 또는 전달 시스템에서 비롯된 것으로, 약제 제품 자체나 그것의 성분과는 관련이 없습니다. 침출물은 약제 제품의 작용으로 포장 또는 전달 시스템에서 약제 제품으로 이동하는 물질들입니다. 따라서, 침출물은 주로 1차 및 2차 포장에서 비롯되며, 이러한 포장들은 약제 제품과 다른 외부 화학 물질들 간의 장벽 역할을 합니다. 그러나 침출물은 포장에서 직접 환자에게 이동할 수도 있습니다.


최근 발생한 recall 사례는 이러한 문제의 심각성을 더욱 강조합니다. Pfizer의 Lipitor, Johnson & Johnson 의 Tylenol 및 Depomed의 Glumetza와 관련된 recall 사례에서, 나무 팔레트에서 발생한 화학 물질인 2,4,6-tribromoanisole이 약물 제품에 침출되어 불쾌한 냄새를 유발한 것으로 밝혀졌습니다. 이 화학 물질은 나무 팔레트에 사용되는 방충제의 부산물로 알려져 있습니다.


TBA는 2,4,6-tribromoanisole의 약자입니다. 이는 나무 팔레트나 포장재에 사용되는 방충제의 부산물에서 발견될 수 있는 화학 물질로서, 때로는 약물 또는 식품 제품에 침출될 수 있습니다. 2,4,6-tribromoanisole은 특정한 양에서 소비될 때 일시적인 위장 질환을 일으킬 수 있습니다. TBA의 오염은 특히 나무 팔레트에서 나오는 냄새 또는 불쾌한 냄새의 주요 원인으로 알려져 있습니다. 


이러한 사례는 침출물이 단순히 포장재에서만 발생하는 것이 아니라, 2차, 3차 또는 4차 포장제에서도 발생할 수 있음을 보여줍니다. 따라서 침출물의 평가와 관리는 약제의 품질과 안전성을 보장하는 데 있어 중요한 고려사항이 되어야 합니다. TBA와 같은 침출물의 위험을 최소화하기 위해서는 적절한 품질 관리 및 테스트 프로토콜이 필요합니다.

“ LeachabLes are a subset of extractables but not all  Leachables are necessarily extractables. “

"침출물(Leachables)은 추출물(Extractables)의 부분집합이지만, 모든 침출물이 꼭 추출물인 것은 아니다."


see also "Migrants"


Genotoxic Impurities Analysis


Pharmaceutical genotoxic impurities analysis services delivered from our GMP labs to support the identification, quantification and control of genotox impurity levels in APIs or drug products to meet regulatory expectations



Genotoxic impurities (GI) analysis is critical to address the purity, safety and quality of drug substances or finished drug products related to potential genotoxic impurities. The ICH M7(R2), a genotoxic impurity guideline defines genotoxicity as “a broad term that refers to any deleterious change in the genetic material regardless of the mechanism by which the change is induced”. There are a range of sources of genotoxic impurities, contributed to reactive materials used in drug substances which have the capacity to interact with human DNA to cause mutations and cancer, even at extremely lowest levels. These substances include a group of potentially high potency mutagenic carcinogens which have “alerting structures” such as N-nitroso-, aflatoxin-like-, and alkyl-azoxy compounds.


Identifying GIs early in the drug development process and/or limiting genotoxic impurities at acceptable levels in the API or drug product, can avoid risks associated with drug safety and quality later in development and/or marketing authorisation, that could potentially lead to expensive recalls. A key example of this are nitrosamine impurities such as N-nitrosodimethylamine (NDMA) which have been highlighted by the US FDA (2018) and other regulatory authorities as an area for concern.


Guidelines from drug regulatory authorities in both Europe and the United States of America (USA) require the control of GIs and potentially genotoxic impurities (PGIs) at parts per million levels in drug substances. Determination of genotoxic impurities at trace levels (lower than 0.01-0.03%) requires highly sensitive and specific analytical approaches that are suitable for the sample matrices of interest and ideally allow detection in the range of 1-to 5ppm.


Our GCP/GLP/GMP compliant laboratories provide genotoxic impurity testing services to detect and evaluate the potential of GIs for your API and/or drug substances which can support your product development from an early stage to market release. With scientists who are adept at method development and validation of suitable analytical procedures, we can overcome the challenges of low detection levels and difficult matrices. Using a range of technologies we can apply an orthogonal approach to ensure robust, specific and sensitive analysis.  Our comprehensive characterisation techniques include: 


  • High Performance Liquid Chromatography with (HPLC with UV/Vis detectors)
  • Gas Chromatography (GC) and GC-MS
  • Liquid Chromatography-Mass Spectrometry (LC-MS)
  • Inductively-Coupled Plasma Optical Emission Spectroscopy
  • (ICP-OES) and Inductively- Coupled Plasma Mass Spectrometry (ICP-MS)
  • Nuclear Magnetic Resonance Spectroscopy (NMR)


As part of our comprehensive stability study capability, we examine degradation products under stressed conditions to help establish degradation pathways. Additionally, we offer highly sensitive and specific method development and validation expertise which is required to address the issues of genotoxic impurities including nitrosamines screening and quantification. 


Toxicological Risk Assessment
With many years of experience in toxicological risk assessments, our consultants conduct risk assessments to address the issues associated with exposure to genotoxic impurities and other substances of concern including residual solvents, process impurities, extractables & leachables, elemental impurities (ICH Q3D) and other substances that may find their way into a pharmaceutical product. 


Total Quality Assurance
Genotoxic impurity testing is one aspect of our global GMP and CMC laboratory services solutions which include pharmaceutical impurity analysis, stability testing, quality control (QC) and batch release testing. Bringing quality and safety to life, we offer Total Quality Assurance expertise to help you to meet and exceed quality, safety and regulatory standards.


Particulate Matter

in an Injectable Drug Product


Particulate contamination is a critical quality attribute for any pharmaceutical. In this case study, our expert, Dr Peter Muehlschlegel describes the steps of an investigation into the occurrence of foreign particulate matter (FPM) in a lyophilised drug product. The composition of FPM was identified through the application of microscopy and spectroscopy techniques which helped to confirm the origin of the particles. The insight from this study then helped to de-risk the production process in relation to FPM.


Standards of producing pharmaceutical products are described within the various pharmacopeias, that include routine test methods for particulates such as:


•  USP <787> Subvisible Particulate Matter in Therapeutic Protein Injections

•  USP <788> Particulate Matter in Injections

•  USP <789> Particulate Matter in Ophthalmic Solutions

•  USP <790> Visible Particulates in Injection / PharmEur 2.9.20. 

•  USP <1788> Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions



Examples of particulate contamination we have helped clients resolve typically involve:


  • Extraneous particulates or fibers presenting as perhaps black specks within powder products or highly coloured material within a more lightly coloured product
  • Residuals from cleaning and maintenance
  • Particles observed upon dissolution or particles of different particle size and/or shape to the bulk of the material
  • Metal abrasion and corrosion leading to extraneous metal particles from pipes, pumps and vessels 
  • Particles stemming from process equipment (e.g. PTFE particles from filters, joints or gaskets)
  • Glass fragments caused by glass delamination or breakage
  • Biological matter of microbiological origin
  • Mineral particles where the manufacturing or geographic origin is important.
  • Rubber, silicone or other polymeric particles  or Teflon particles from filters, joints or gaskets



GMP-Compliant DNA Sequencing service


articulate Matter

in an Injectable Drug Product


Established cGMP Sanger sequencing service for release testing of regulated biological drugs as well as for validation of DNA-based diagnostic tests/devices for market clearance applications. Whether you wish to make a European or FDA-level submissions, quality system has been set up to meet the most stringent quality requirements from regulatory authorities worldwide.

Features and Benefits

Applications

High Quality
  • 2-fold or 4-fold coverage sequencing service available
  • All analyses performed according to GMP requirements
  • Guaranteed accuracy of final data >99.999% per base
  • Quality assurance statement (ISO/IEC 17025 (STS 429) and GMP Swissmedic 20-0362)

Accurate
  • Fast turnover time due to in-house synthesis of primers
  • Plasmid isolations under GMP conditions for GMP samples
Professional Project Handling
  • Each project is guided by a designated study director
  • Evaluation of each chromatogram
  • Sequence verification against a known reference sequence including mutation detection or de novo sequencing
Reporting & Documentation
  • Assembly of sequence data and detailed sequencing strategy reporting
  • Extended GMP project reporting
  • Archiving of samples and data for 10 years (longer times available on request)

Experience
  • Experienced with the management of GMP projects for international major pharmaceutical companies


GMP Biologics Lot Release
  • Sanger sequencing is applied as QC for final lot release of plasmid DNA and viral products used for biologics manufacturing
DNA/RNA identity and stability studies
  • Sanger sequencing is used for identity and stability tests of various cell banks, plasmids, viruses and vaccines
Genetic testing for preclinical and clinical testing
  • Sanger sequencing is utilized as “Gold Standard” method to analyze clinical trial samples (e.g. for SNP detection) or to validate assays to be used in preclinical or clinical trials
Validation of in vitro DNA-based diagnostic assays
  • Sanger sequencing is used as “Gold Standard” method to validate nucleic acid based diagnostic assays or devices for regulatory clearance.



Saint-Gobain

Silicone pump tubing


Benefit : 

Low spallation 

Accutate


for Final fill


Low Spallation

Sani-Tech® SPT-60L has the lowest spallation (number of particles and area of particles) across multiple dispensing cycles among the various silicone pump tubing evaluated.

Sani-Tech® SPT-60L


Pump Tubing for

High Accuracy Applications

Features / Benefits

•Long Pump Life

•Low Spallation

•Accurate and Consistent Dispensing

•Full Extractables Report per BioPhorum  Operations Group (BPOG) Protocol

•Technical Dossier Available

•Available with ValPlusTM Certification  (See page 4 for more details)

Typical Applications

•Final Fill

•Extended Duration Pumping

•Precision Pumping

Video: ValPlus™ - Enhanced Tubing Validation

ValPlus™ is an enhanced validation package offered on Saint-Gobain Life Sciences tubing which provides certification that bioburden, endotoxin and particulate criteria are met. This may allow for reduced validation at the bioprocessing facility, which increases speed to market and reduces validation costs.








Saint-Gobain KOREA Life Science Agency

(주)큐비디

A world leader in the development and integration of innovative materials and components, we create customized single-use solutions for the biopharmaceutical and cell therapy markets. Through our unparalleled technological expertise and worldwide resources, we develop integrated solutions for critical fluid management to meet your evolving needs.

Fluid Transfer

Filtration

Single-Use Assemblies

Containment


Custom design example for overmolding and Single use assembly

- 생고뱅 인천 송도공장 제조 ( ISO Class 7 ) -