1. 개요(Introduction) ·························································································································· 1
2. 적용범위(Scope) ····························································································································· 1
3. 용어정의(Glossary) ························································································································ 1
4. 공정 특성확인(Process Characterization) ················································································ 4
4.1. 공정의 개발 ······························································································································· 4
4.2. 공정의 평가 ····························································································································· 4
5. 공정 밸리데이션(Process Validation) ······················································································· 6
5.1. 전통적 공정 밸리데이션 ········································································································· 6
5.2. 공정의 확인 ······························································································································· 7
5.3. 지속적 공정 확인 ····················································································································· 8
5.4. 조합방식의 접근방법 ··············································································································· 9
5.5. 설계공간 확인··························································································································· 9
6. 고려사항(Considerations) ··········································································································· 10
6.1. 일반적 고려사항····················································································································· 10
6.2. Upstream 공정 ························································································································ 11
6.2.1. 공정별 중요품질속성 ·········································································································· 12
188.8.131.52. 배양공정····························································································································· 12
184.108.40.206. 회수공정····························································································································· 13
6.2.2. Upstream 공정의 평가······································································································· 14
6.2.3. Upstream 공정의 확인······································································································· 14
6.2.4. 단회사용 장비의 사용········································································································ 14
6.2.5. 다중회수 관련 문제 ············································································································ 15
6.3. Downstream 공정 ················································································································ 15
6.3.1. 정제공정 중요품질속성 ······································································································ 16
6.3.2. Downstream 공정의 평가 ································································································· 17
6.3.3. Downstream 공정의 확인 ································································································· 18
6.3.4. 재가공···································································································································· 18
6.3.5. 정치시간, 보관 및 운송 ····································································································· 18
6.4. 완제공정 중요품질속성········································································································· 19
6.5. 다중시설을 사용하는 생산 ··································································································· 20
7. 제조규모의 확대(Scale-up) ········································································································ 20
8. 공정의 변경(Post approval change control) ········································································ 21
9. 참고문헌(References) ·················································································································· 21
<첨부 1> 일반적인 제조공정 밸리데이션의 절차 ·································································· 22
1. 관련 용어의 정의 ························································································································22
2. 사전 준비 사항 확인 ··················································································································22
3. 밸리데이션 실시계획서 작성 ·································································································· 22
4. 제조공정 밸리데이션 실시······································································································ 23
5. 밸리데이션 결과보고서 작성 ·································································································· 23
6. 공정 중 검체의 채취 및 분석방법 ························································································ 24
<첨부 2> 밸리데이션에서의 품질위험관리(QRM) 적용[참고사항] ···································· 25
1. 품질위험관리 관련 용어 ············································································································ 25
2. 품질위험관리를 위한 팀구성···································································································· 26
3. 위험요소진단(Risk Assessment) ······························································································· 26
4. 위험요소조절(Risk Control) ······································································································ 27
5. 위험정보교환(Risk Communication) ······················································································· 27
6. 위험요소검토 및 문서화(Risk Review and Documentation) ············································ 27
7. 품질위험관리의 분석방법 ·········································································································· 28
생물유래 원료를 사용하여 제조되는 바이오의약품은 화학합성의약품과는 달리
공정 변수가 다양하고 각별히 주의를 기울여야 하는 공정이 많다.
이 가이드라인은 바이오의약품의 제조공정별 중요한 공정변수와 품질속성을
고려한 공정밸리데이션의 설계와 검증에 있어서, 최근의 국제적 추세와 방향을
반영하여 제조 현장에서 참고할 수 있도록 하기 위해 마련하였다.
2. 적용범위(S cope)
이 가이드라인은 생물학적제제, 유전자재조합의약품 등 바이오의약품의 제조
다만, 공정밸리데이션의 일반적 적용범위, 실시방법 등이 의약품 등의 안전에
관한 규칙 [별표 1] ‘의약품 제조 및 품질관리기준’, [별표 1의2] ‘원료의약품
제조 및 품질관리기준’ 및 의약품 제조 및 품질관리에 관한 규정 (식품의약품
안천처고시)에 규정된 경우 이를 따라야 한다.
이 가이드라인에서 사용되는 용어는 다음과 같이 정의한다.
가. “바이오의약품”이란 사람이나 다른 생물체에서 유래된 것을 원료 또는 재료로
하여 제조한 의약품으로서 보건위생상 특별히 주의가 필요한 의약품을
말하며, 생물학적제제, 유전자재조합의약품, 세포배양의약품, 세포치료제,
유전자치료제, 기타 식품의약품안전처장이 인정하는 제제를 말한다.
나. “공정밸리데이션(Process Validation, PV)”이란 설정된 범위 이내에서 제조했을
때 사전에 설정된 규격과 품질 특성에 부합하는 의약품을 효과적이고 재현성
있게 생산할 수 있음을 검증하고 이를 문서화하는 것을 말한다.
다. “중요품질속성(Critical Quality Attribute, CQA)”이란 원하는 원료의약품
및 완제품 품질을 보장하기 위하여 적절한 한도, 범위 또는 분포 이내에 있어야
하는 물리적, 화학적, 생물학적 또는 미생물학적 특징이나 특성을 말한다.
라. “공정평가(Process Evaluation)”란 소규모 또는 상업규모에서 수행된 것으로서
전체 제조공정과 각 공정 작업단위에서 얻고자 한 품질의 제품을 제조하는데
적절하게 설계되고 관리됨을 증명할 수 있는 증거를 확보하는 것이다.
마. “공정설계(Process Design)”란 개발 및 제조규모 확대 등을 통해서 얻은
지식에 근거하여 상업규모 제조공정을 결정하는 것을 말한다.
바. “입증된 허용범위(Proven Acceptable Range, PAR)”란 품질 허용기준에
적합한 제품을 생산할 수 있음이 입증된 범위 내에서 작업할 수 있는
공정변수의 특정된 범위를 말한다.
사. “전주기(Lifecycle)”이란 제품의 초기 개발부터 생산, 판매, 사용, 제품공급
중단에 이르기까지의 모든 단계를 말한다.
아. “브라캐팅 방법(Bracketing Approach)”이란 공정밸리데이션을 수행하는
동안에 농도, 배치 크기, 포장 크기 등 미리 정해지고 정의된 설계요소
등에 해당하는 경우에 특정한 배치에서만 시험하도록 설계하는
밸리데이션 계획을 말한다. 이 방법은 동일한 용기시스템을 적용하나 용기
크기 또는 충전량이 다른 경우에 적용할 수 있다.
자. “공정확인(Process Verification)”이란 최종 제조공정이 효과적으로 수행되고
사전에 결정된 허용기준에 맞는 원료의약품 또는 중간제품을 생산할 수
있음을 상업적 규모로 제조한 적절한 수의 배치를 사용하여 확증하는
차. “지속적 공정 확인(Continuous Process Verification)”이란 제조공정의
성능을 연속적으로 모니터링하고 평가하는 방식을 이용하는 공정밸리데이션의
카. “관리전략(Control Strategy)”이란 공정의 성능과 제품의 품질을 보증하는
현재의 제품과 공정에 대한 이해를 바탕으로 계획된 관리체계를 말한다.
이 때 관리에는 원자재, 원료의약품 및 완제품에 관련된 공정변수와
특성요소, 시설 및 장비의 운영조건, 공정검사, 완제품의 규격, 이들에
관한 모니터링과 관리의 방법과 주기를 포함될 수 있다.
타. “인라인(in-line)”이란 공정 진행 중인 중간체 제품에 대하여 검체를 공정으로부터
분리하지 아니하고 공정 진행 상태에서 검체를 분석하는 방법이다.
파. “온라인(on-line)”이란 공정 진행 중인 중간체 제품에 대하여 공정중에
검체채취용 배관을 통하여 검체를 채취하여 분석하는 방법이며, 채취된
검체는 공정에 재투입되지 않는다.
하. “앳라인(at-line)”이란 공정 진행 중인 중간체 제품에 대하여 검체를 채취,
분리하여 근접 거리에서 분석하는 방법이다.
거. “중요공정변수(Critical Process Parameter, CPP)”란 공정변수 중 변동이
발생하면 중요품질속성에 영향을 주므로 공정이 원하는 품질을
생산하도록 하기 위해 모니터 또는 관리해야 하는 공정 변수를 말한다.
너. “공정분석기술(Process Analytical Technology)”이란 원료, 공정 진행 중인
중간체 및 공정의 품질과 성능특성에 대하여 당해 공정을 완료한 후
생산된 최종 제품의 품질을 보증하기 위하여, 실시간 측정 또는 공정 중
신속한 측정을 바탕으로 한 제조공정의 연속적 분석 및 관리체계를 말한다.
더. “설계공간(Design Space)”이란 제품의 품질이 크게 변하지 않는다고 확신할
수 있는 공정변수별 범위로 구성된 영역을 말한다. 품질 보증과의
연관성이 증명된 공정변수와 투입변수(예, 물품 특성 요소)의 다차원적
조합과 상호작용을 포함하며, 설계공간 내에서의 작업은 변경으로
간주되지 않는다. 설계공간을 벗어나는 것은 변경으로 간주되며
일반적으로 규제기관에 변경 신청을 해야 한다. 설계공간은 신청업체가
제안하며 규제기관의 평가와 승인을 받는다.
러. “정치시간(Hold Time)”이란 공정 작업단위의 서로 다른 단계에서 특정
중간체를 보관하는 데 제한된 시간을 말한다. 이것에 관한 연구는 그
정치시간 동안 제품의 품질이 저하되지 않음을 보증하기 위해 수행된다.
4. 공정 특성확인(Process Characterization)
공정 특성확인은 계획된 표준 공정 및 관리 문서에 반영될 상업생산 규모의
공정을 정의하는 활동이다. 이 단계의 목표는 제조하고자 하는 바이오의약품이
품질속성에 맞게 지속적으로 생산될 수 있도록 상업생산 규모에 적합한 공정을
설계하는 것이다. 공정 특성확인은 공정의 개발과 공정의 평가로 나눌 수 있다.
4.1. 공정의 개발(Process Development)
‘공정개발’의 목표는 얻고자 하는 품질의 제품을 지속적으로 생산할 수 있는
상업생산 규모에서의 제조공정을 수립하는 것이다. 공정개발은 향후 수행될
‘공정의 평가’와 ‘공정의 입증’ 단계에서 적용할 허용기준과 조건을 정하는 데
필수적인 역할을 한다. 보다 자세한 사항은 ICH Q11을 참조한다.
공정개발에는 제조공정의 설계를 도출하기 위한 연구가 포함된다. 공정개발
단계에서는 공정의 평가 및 입증 시에 검토되어야 할 각 공정 또는 단위작업에
투입되는 원자재 특성 및 공정변수와 당해 공정결과물의 품질속성, 세포수 및
수율 등과 같은 성능지표를 정하여야 한다.
문서화된 사전 지식과 위험평가는 바이오의약품의 중요품질속성(CQA)과
공정의 성능에 잠재적 영향을 줄 수 있는 원료(출발물질 포함), 시약, 용매, 공정
중 첨가제, 중간제품 등 원자재의 특성과 공정변수를 확인하고 정하는데
유용하게 사용할 수 있다.
4.2. 공정의 평가(Process Evaluation)
‘공정평가’는 개발된 제조공정 및 공정관리 기준에 따라 작업할 때 전체공정
및 각 공정 단위작업에서 얻고자 한 품질의 제품을 제조하기에 적절하게
설계되고 관리되는지를 확인하는 것이다. 성공적인 공정평가는 관리전략에 따라
사전에 정의된 작업 범위를 적용한 공정설계가 상업생산 규모에서도 적절하게
재현되는지를 보여 주어야 한다.
공정의 잠재적 중요도에 따라 투입물과 산출물을 정하여 시험하여야 하며 그에 대한
타당성을 기술하여야 한다. 시험을 수행하지 아니한 경우, 그것들이 제품의 품질에
영향을 미치지 않는 범위 내에서 유지된다는 타당한 이유를 설명할 필요가 있다.
공정평가는 설정된 공정과 공정관리 기준에 따라 수행했을 때 소규모 또는
상업생산 규모에서 최종제품이나 중간제품이 적절하게 생산되는지 확인할 수
있도록 각 단계에 대한 성능평가를 포함하여야 한다. 공정의 투입물과 산출물은
각 단계별로 기술되어야 한다. 이러한 자료는 계획된 투입 범위 내에서
작업했을 때 결과물이 적절한 품질 허용기준(즉, 미리 정해진 허용기준 또는
자체 기준) 내에 있고 입증된 허용범위(PAR)가 적절한지를 증명해야 한다.
공정평가의 결과는 관리전략을 결정하기 위한 중요한 근거가 되며, ‘공정입증’을
위한 허용범위를 결정하는데 사용된다. 관리전략의 요소들은 공정입증의 결과에
따라 최적화될 수 있다.
플랫폼 자료 등 사전 지식은 보조적인 정보로 사용될 수 있다. 밸리데이션을
위하여 이러한 자료의 활용은 예정된 상업생산 규모의 제조공정을 대표하는
자료로 인정할 수 있을 때 가능할 것이다.
특정 공정단계에서의 최악조건 평가는 그러한 조건에서 얻고자 하는 품질의
제품을 생산하기 위한 당해 공정의 견고성과 성능을 증명하거나 보조하기 위해
수행될 수 있다.
바이오의약품 제조공정의 개발 및 평가에 있어서 소규모생산 모델은 중요한
수단이다. 공정평가 기간 동안 소규모생산 모델은 상업적 제조규모에서 적용할
수 없는 원자재 투입 및 공정변수의 변동성을 평가할 수 있다.
소규모생산 모델은 제조공정의 적절한 대표성을 가질 수 있도록 설계되고,
수행되고, 궁극적으로 정의되도록 하여야 한다.
소규모생산 모델이 사용된 경우에 목적, 설계, 투입물 및 산출물에 관하여
설명되어야 하고 상업생산 규모에서의 타당성이 정의되어야 한다. 소규모생산
모델이 밸리데이션에 크게 영향을 줄 때, 대표성을 가진 투입물을 사용하는
동일한 조건 하에서의 작업과 상업생산 규모의 공정 산출물이 소규모생산
모델과 일치하는지 증명하여야 한다. 작업조건, 투입물 또는 산출물에서의
차이점이 발견되었을 때는 적절하게 언급되어야 한다. 발견된 차이점과 그에
대한 이해에 관하여는, 문서화 및 정의가 잘 되어 있는 경우라면 이러한
차이점들을 관리하는 방식[예, DOE(Design of Experiments)가 사용된 경우에
조정요소의 사용]이 받아들여질 수 있다. 이러한 접근방식을 사용할 경우,
불확실성과 관련한 위험에 대해서는 관리전략을 사용하는 등 적절한 관리가
원자재 또는 공급업체의 변경 등으로 인해 특정 원자재가 제품 품질에 잠재적
영향을 줄 수 있는 가능성을 고려하여 원자재의 영향에 대하여 언급되어야
한다. 이러한 부분은 소규모에서, 가능하면 개발단계의 초기에 계획되어야 한다.
이 때 원자재가 제품 품질에 어떤 영향을 미치는지 그 연관성을 확인하기 위해
위험기반의 접근방법이 적용될 수 있으며, 제품의 전주기 전반에 걸쳐 원자재와
관련된 위험이 관리되어야 한다.
㈜서호 전북 전주시 덕진구 혁신로 586 (54851)
Tel. 063-214-9325 / Fax. 063-214-9328