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    제약/바이오전문 1등 헤드헌팅사 나우팜컨설팅

    CMC와 ADME 용어 설명-나우팜컨설팅 하영권박사

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    관리자 21-02-22 12:01

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    CMC란?
    CMC는 화학합성(Chemistry), 공장생산(Manufacturing), 품질관리(Control 또는 quality control)의 요약이다. 신약개발에서 전임상·임상용 시험약을 만들어 주고, 인허가 획득 후에는 출시를 목적으로 의약품의 대량 생산을 담당하는 곳을 CMC부서라고 한다.
     
    CMC는 원료의약품(drug substance 또는 API, Active Pharmaceutical Ingredient)와 완제품(drug product) 등으로 나뉜다. 이 중 화학합성 또는 생물학적 절차를 통해 만들어지고 약효가 있는 주요물질(APl)을 원료의약품(drug substance)이라고 말하고, 1개 또는 1개 이상의 원료의약품을 가지고 제제연구를 통해 환자에게 투여될 완제품(경구용 고형약제, 주사제, 패취제 등)은 `drug product`라고 정의한다.

    CMC – Chemistry, Manufacturing and Controls
    To appropriately manufacture a pharmaceutical or biologic specific manufacturing processes, product characteristics, and product testing must be defined in order to ensure that the product is safe, effective and consistent between batches.  These activities are known as CMC, chemistry, manufacturing and control.

    All stages of the drug development life cycle, after drug discovery involve CMC.  During preclinical drug development, the proper analytical methods are validated to monitor the product.  Stability testing may be initiated, the physicochemical properties of the product are determined, raw materials are chosen and tested.  When the drug development process moves into the clinical stage, further analytical method validation is required, and additional characterization of the drug product is needed.  After clinical trials the scale up process must ensure that the larger batches of product are the same and meet the same specifications as the drug tested in the clinical trials.  After the manufacturing process is qualified, lot release and in process testing will continue to take place.

    In this section of the learning center we explore CMC requirements of different products.  Small molecules, large molecules and gene therapy products all have very different requirements, but each share the same purpose, to ensure that the manufacturing process consistently produces a safe and effective product that meets or exceeds the specifications set in the NDA.

    ADME란?

    흡수 분포 대사 배설(ADME)은 약물동태학에서 흡수(absorption), 분포(distribution), 대사(metabolism), 배설(excretion)을 의미하며, 생물체 내에서의 약품의 분포를 묘사한다.

    이 4가지 기준 모두 약의 수준과 조직의 노출에서의 약의 반응 속도론에 영향을 미치며 그러므로 영향과 화학약품의 약리학 활동에 영향을 미친다.

    1. 흡수(Absorption)
    2. 분포(Distribution)
    3. 대사(Metabolism)
    4. 배설(Excretion)

    흡수(Absorption)
    화합물이 조직에 도달하기 위해, 이것들은 그것들이 표적세포에 의해서 차지되기 전에 혈류에 들어 가야했다(보통 위장관의 내장흡수같이 점액표면을 통해서). 낮은 화합물 융해도, 위내정체시간, 장 변형 시간, 위 속의 화학 불안정성과 위벽이 흡수하지 못하는 것 과 같은 요인들은 모두 경구 투여 후 흡수되는 시간을 줄일 수 있습니다. 흡수는 생물학적 이용 가능성 복합체를 분명하게 측정합니다. 경구로 흡수될 때 제대로 흡수되지 못한 약물들은 반드시 덜 바람직한 방식으로 투여되어야 한다. 정맥치료나 내 흡입에서처럼.

    분포(Distribution)
    복합체들은 대부분의 경우 혈류를 통해 주효 세포로 옮겨질 필요가 있다. 그곳으로부터 복합체들은 아마 상이한 차이로 근육과 장기로 나뉠 것이다. 체순환이 된 후에, 맥관 내 주사에 의해 혹은 어떤 다양한 세포 외 위치에 의해서 그 약물은 혈장농도를 낮추는 경향이 있는 수많은 배포과정을 받을 것이다.
    배포는 한 구역에서의 다른 구역으로의 가역 전달로 정의된다. 몇가지 약물 배포에 영향을 미치는 요인들은 부분의 혈류량과, 분자의 크기, 양극성 그리고 혈청 단백질을 굳히는 것과 복잡한 구조 형성을 포함한다. 배포는 혈액 내 관문 같은 자연적인 관문에서는 심각한 문제가 될 수 있다.

    대사(Metabolism)
    복합체들은 몸속에 들어가자마자 깨지기 시작한다. 소형세포약물 신진대사의 대부분은 cytochrome P450 enzymes이라고 명명된 간의 산화환원요소에 의해서 수행된다. 신진대사가 일어남에 따라, 최초의 복합체들은 대사산물이라고 불리는 새로운 복합물들로 바뀌게 된다. 대사산물이 약물학적으로 활발하지 못하게 되면, 신진대사는 모의약품의 공급된 투여량의 활동을 정지시킨다 그리고 이것은 보통 신체에 대한 효능을 줄인다. 대사산물은 아마 또한 약물학적으로, 가끔 모의약품의 효능보다 활발히 활동할 수 있다.

    배설(Excretion)
    약물배설이 발생할 때 3가지의 주요 장소가 있다. 신장이 가장 중요한 장소이고 소변을 통해서 생성물물들이 배출되는 장소이다. 담즙 배설 혹은 대변 배설은 간에서 시작하는 과정이고 생성물들이 찌꺼기 혹은 대변과 함께 배설될 때까지 소화관을 거친다. 마지막 배설의 주요 과정은 폐를 거친다.



    ADME?
    What are the four steps of pharmacokinetics?
    Pharmacokinetics is a specific branch of pharmacology that studies what the body does to a drug. Pharmacokinetic studies evaluate:

    The rate that a chemical is absorbed and distributed
    The rate and pathways of drug metabolism and excretion
    The plasma concentration of a drug over time ADME are the four steps of pharmacokinetics. Let us break down what each of these steps involves.

    Absorption
    Absorption describes how a chemical enters the body. Absorption relates to the movement of a chemical from the administration site to the bloodstream.
    There are four main routes of administration:
    Ingestion through the digestive tract
    Inhalation via the respiratory system
    Dermal application to the skin or eye
    Injection through direct administration into the bloodstream
    Only injected compounds enter directly into the systemic circulation. For drugs administered through ingestion, inhalation or dermal contact, the chemicals must cross a membrane before entering the bloodstream.

    There are 4 ways through which a chemical can cross a membrane and enter the bloodstream.

    1. Passive diffusion: When a molecule moves from an area of high concentration to an area of low concentration. This is the most common way a drug is absorbed.
    2. Facilitated diffusion: When a molecule moves from an area of high concentration to one of low concentration with the help of carrier proteins in the membrane.
    3. Active diffusion: An energy-dependent process during which a molecule requires energy in the form of ATP to cross a membrane. 
    4. Endocytosis: When a larger drug is transferred through a membrane via invagination of the membrane.

    The route of administration influences bioavailability, which is a measure of how much of a drug is absorbed in an unchanged form. You can find the bioavailability by measuring the plasma drug concentration over time. Only intravenous administration results in 100% bioavailability. Drugs administered in other ways will have reduced bioavailability. Not all of the compound will make it into the bloodstream. For instance, a drug that is ingested first undergoes metabolism during which some of the drug is excreted before entering the bloodstream.

    Distribution
    Once a drug has been absorbed, it moves from the absorption site to tissues around the body. This distribution from one part of the body to another is typically accomplished via the bloodstream, but it can also occur from cell-to-cell.

    Researchers examine where the chemical travels to, the rate at which it arrives to certain sites, and the extent of the distribution to help determine efficacy. Some compounds move easily, while others do not. Factors such as blood flow, lipophilicity, tissue binding, and molecular size influence distribution.

    Metabolism
    Drug metabolism is the biotransformation of a drug by organs or tissues (primarily the liver, kidney, skin or digestive tract) so that the drug can be excreted. To facilitate removal via feces or urine, the drug compound is altered to become more water-soluble.

    Chemical metabolism can result in toxicity, for instance by creating damaging biproducts or a toxic metabolite. Scientists map out the specific metabolic pathways of a drug candidate, something called adverse outcome pathways (AOPs). AOPs provide data needed to determine the potential safety or toxicity of a drug.

    Drug metabolism and interaction data provide researchers with the information they need to determine the likelihood of drug–drug interactions (DDIs). Anticipating drug interactions is essential for safe pharmaceutical development.

    Excretion
    Excretion is the process by which the metabolized drug compound is eliminated from the body. Researchers want to know how rapidly the drug is excreted and what pathway it takes to exit the body. Most drug excretion occurs as feces or urine. Other excretion methods include through the lungs or in sweat through the skin. Molecular size and charge influence the excretion pathway.

    Not every drug compound is fully excreted. When the chemical or metabolic by-products bioaccumulate, adverse effects can occur. Lipid-soluble compounds are more prone to bioaccumulate compared to water-soluble compounds.

    Why is ADME important?
    In drug discovery and development, researchers must examine the activity of a drug in the body to assess safety and toxicity. Drug metabolism and pharmacokinetics studies, such as ADME and toxicology studies, are a critical step in this process. The data collected tells researchers if a drug is viable and provides specific targets for future research and development.