ER/ES実践について研究するページです。
＊万が一文中に解釈の間違い等がありましても、当社では責任をとりかねます。
本文書の改訂は予告なく行われることがあります。
ERESガイドライン対応のための課題と問題点（その2）
1. はじめに
前回に引き続き、ERESガイドライン対応のための課題と問題点を整理してみたい。
ERESガイドラインは、言うまでもなく日本国内における指針である。しかしながらグローバル化が進む製薬業界において、ERESガイドラインを遵守するのみではすまされない。グローバルな企業にとって、ERESガイドラインとPart11などの諸外国の規制要件が整合しない場合、いわゆるダブルスタンダードの問題がおきる。
今回はPart11や、その他関連ガイダンスも引用し、検討を行ってみたい。
2. コンピュータ・システム・バリデーション
ERESガイドラインを遵守する前提として、コンピュータ・システム・バリデーション（以下、CSV）を実施しなければならない。（図1参照）
| 3.1. 電磁的記録の管理方法 電磁的記録利用システムとそのシステムの運用方法により、次に掲げる事項が確立されていること。この場合、電磁的記録利用システムはコンピュータ・システム・バリデーションによりシステムの信頼性が確保されている事を前提とする。 |
図1 コンピュータ・システム・バリデーション
しかしながら厚生労働省では、拠り所とするべき具体的なCSVに関する指針などの規制要件を発行していない。
当局から指針等が出されない場合、製薬各社がCSVに関するSOP等を作成したとしても、それらの「適合性の確認」が行えない。これは品質保証活動（以下、QA）上の大きな問題である。
「適合性の確認」は、規制要件と自社のSOPを照し合せて、それらに差異がないことを確認する。この適合性をもったSOPによって、品質管理システム（Quality Management System：QMS）が成り立つのである。
ちなみにFDAでは、2003年9月に発行した「Part 11, Electronic Records; Electronic Signatures ? Scope and Application」において「コンピュータ・システムのバリデーションに関する詳しいガイダンスについては、FDAによる業界およびFDAスタッフ向けのガイダンスである、FDA staff General Principles of Software Validation およびGAMP 4 Guideといった業界向けのガイダンスを参照のこと。」と述べている。
2008年2月には、ISPEからGAMP 5が発行された。今後欧米の多くの製薬会社はGAMP 5に準拠したCSV SOPを作成し、CSVを実施することになると思われる。
おそらく日本の製薬企業も同様にGAMP 5等を参考にしてCSV SOPを作成しCSVを実施することになると思われるが、前述の通り規制当局が拠り所とする指針等を発行し、FDAのようにGAMP 5等を参照することと明記することが望まれる。
ちなみにPart11でもCSVは前提条件であり、§11.10 (a)に次のように記載されている。
「Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.（正確性、信頼性、意図した性能の一貫した確保、ならびに無効となったり変更されたりした記録を識別する能力が保証されるようにするためのシステムのバリデーション）」
意外と知られていないことであるが、FDAはPart11の発行をもってバリデーションの定義を変更した。この条文にあるように従来のバリデーションに加えて「無効となったり変更されたりした記録を識別する能力」すなわち「修正証跡（監査証跡）」を要求している。修正証跡（監査証跡）機能がないシステムは、Non-Validateである。
3. ハイブリッドシステム
電子の記録を利用するが、電子署名は使用せず、記録を紙媒体に印刷したものに手書きの署名を付す方法をハイブリッドシステムと呼ぶ。
考えてみれば、製薬企業の記録の大部分はハイブリッドシステムで成り立っている。逆の言い方をすれば、ペーパーレス（すなわち電子署名を利用しているシステム）は、EDCシステムや安全性電子報告システム等に過ぎない。eCTDも現在のところ署名ページをスキャンニングし提出している。
FDAは、Part11のSub Part B「Electronic Records」とSub Part C「Electronic Signature」は別々の要件としてとらえて良いと述べている。Part11では、電子記録は使用するが電子署名を利用しないといったハイブリッドシステムの利用を想定し、手書き署名に関しても言及している。
しかしながらERESガイドラインでは、ハイブリッドシステムに関する記述は見当たらない。つまり電子記録を利用し、記録を紙媒体に印刷したものに記名・捺印または手書きの署名を付す場合の要件である。
ただし通知文の「3. 適用範囲」には、
「資料、原資料、その他薬事法及び関連法令により保存が義務づけられている資料を紙媒体で作成する際に電磁的記録及び電子署名を利用する場合にあっても、可能な限り本指針に基づくことが望ましいこと。」とある。
4. 電磁的記録媒体への出力
ERESガイドラインでは、見読性の要件のひとつとして、電磁的記録媒体へのコピーをあげている。（図2参照）
この条文はPart11を参考にしているものと思われる。
すでに本シリーズで解説した通り、電磁的記録媒体へのコピーとは、書面に印刷する代わりに、書面と同様の形式でpdf等でCD-R等の電磁的記録媒体に出力することを指している。したがって、ここでは「コピー」ではなく「出力」と読み替えた方が理解しやすい。
| 3.1.2.電磁的記録の見読性 電磁的記録の内容を人が読める形式で出力（ディスプレイ装置への表示、紙への印刷、電磁的記録媒体へのコピー等）ができること。 |
図2 電磁的記録媒体へのコピー
5. 電子署名
電子署名に関しては、本シリーズで幾度となく取り上げてきた。
解説の繰り返しは避けるが、ERESガイドラインにおける電子署名の問題点は、電子署名法に従うこととしたことである。
電子署名法による電子署名（つまり認証局により認証を受けたデジタル署名）は、FDAをはじめグローバルの標準と整合しない。
このままでは、EDCシステムを利用したグローバル治験等に影響が出てしまうのである。
はたして製薬各社は、治験責任医師等がEDCにより電子的にCRFを作成または変更する際に、電子署名法に基づいた電子署名を利用させることができるのであろうか。
また外国製のEDCシステムは、電子署名法に基づいた電子署名の機能を搭載するであろうか。
しかしながら、ERESガイドラインのみではなく、厚生労働省令第44号にも電子署名法に基づいた電子署名の使用が明記されている。
例えば、GCPに従い必須文書として電子CRFを医療機関が保存する場合、電子署名法に基づいた電子署名が付されていなければ、厚生労働省令第44号に違反することとなる。
厚生労働省令第44号およびERESガイドラインが改定されない限り、電子署名（ペーパーレス）は利用を控えた方が無難であるかも知れない。
6. クローズド・システムとオープン・システム
ERESガイドラインでは、Part11と同様にクローズド･システムとオープン・システムに関する記載がある。
「3.2. クローズド・システムの利用」（図3参照）は、条文が意図する事柄が筆者には不明である。特別にクローズド･システムに特化した要件が記載されているとは思えない。
| 3.2. クローズド・システムの利用 電磁的記録を作成、変更、維持、保管、取出または配信をするためにクローズド・システムを利用する場合は、3.1 に記載された要件を満たしていること。また、電子署名を使用する場合には、4. に記載された要件を満たしていること。 |
図3 ERESガイドラインにおけるクローズド・システムの利用
さらに「3.3. オープン・システムの利用」（図4参照）は、筆者には難解である。
「デジタル署名」の使用は、オープン・システムの利用時に特化した追加手段の一例であるとしている。しかしながら電子署名を使用する場合には、4. に記載された要件を満たすことを求めている。
つまりERESガイドラインでは、電子署名とデジタル署名を区別しているように読み取れる。しかしながら「デジタル署名」は「電子署名」という行為を実現するための技術であることから、本来区別することはできないはずである。
| 3.3. オープン・システムの利用 電磁的記録を作成、変更、維持、保管、取出または配信をするためにオープン・システムを利用する場合は、3.1 に記載された要件に加え、電磁的記録が作成されてから受け取られるまでの間の真正性、機密性を確保するために必要な手段を適切に実施すること。追加手段には、電磁的記録の暗号化やデジタル署名の技術の採用などが含まれる。さらに、電子署名を使用する場合には、4. に記載された要件を満たしていること。 |
図4 オープン・システムの利用
余談であるが、Part11は現在改定作業中であるが、改定後はクローズド･システムとオープン・システムを特に区別しないことになると聞いている。
7. 21 CFR Part 11との相違
7.1 国際的な整合性
ERESガイドラインとPart11の関連性及び国際的な整合性に関して、パブリックコメントの回答に記載がある。（図5参照）
| #142 本指針とPart 11は、両者ともに電磁的記録と電子署名に関する要件を規定している点で関連があります。 #144 国際的な整合性については、海外における規制動向等もふまえ、随時対応していく予定です。 #145、#147 （電子記録・電子署名について日・米・欧3極で）基本的な概念は同じであると考えます。現行の内容は、欧米の方向性を十分に考慮されているものと考えています。 |
図5 国際的な整合性に関するパブリックコメントの回答
ERESガイドラインとPart11が完全に整合しない限り、日本の製薬企業ではいわゆる「ダブルスタンダード」の問題が出てくる。
当該電磁的記録が日本国内のみの適用であれば問題がないのであるが、米国へ申請・報告等を行う場合や、EDCを利用してグローバル治験を実施する際などに問題が起きる可能性がある。
7.2 スコープの違い
ERESガイドラインでは、適用範囲を以下のように定めている。
- 薬事法及び関連法令に基づいて、医薬品、医薬部外品、化粧品及び医療機器の承認又は許可等並びに適合性認証機関の登録等に係る申請、届出又は報告等にあたって提出する資料として電磁的記録又は電子署名を利用する場合
- 原資料、その他薬事法及び関連法令により保存が義務づけられている資料として電磁的記録及び電子署名を利用する場合
一方Part11では、図6のように記載されている。
| §11.10(b) 「This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to the agency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if such records are not specifically identified in agency regulations.」 （この条項はFDAの規則で記録が要求されていることに伴い、作成されたり変更されたり、保持されたり、保管されたり、検索されたり、配信されたりする電子形式の記録に適用される。この条項はまた、Federal Food, Drug, and Cosmetic ActおよびPublic Health Service Actに規定された要件にもとづきFDAに提出する電子記録にも、そのような記録についてFDAの規則に明確な指定がない場合においても適用される。） |
図6 Part11におけるスコープ
前回も述べたとおりERESガイドラインは、資料を電磁的記録により提出する場合と、原資料等を電磁的記録により保存する際に適用される。これはもともとeCTDを対象に検討された経緯があるからであると思われる。
これに対してPart11は、もともとGMPにおける製造記録のペーパーレス化（つまり手書き署名を割愛し、電子署名の使用を認める）を目指したものであったことから、記録全般に適用されているものと思われる。
7.3 アプローチ
FDAは2002年8月21日のFDA NEWSで、GMPを改定し21世紀のcGMPのイニシャティブのひとつとしてリスクベースアプローチを採用することを発表した。
これを受けてFDAが2003年9月に発行した「Guidance for Industry － Part 11, Electronic Records; Electronic Signatures ? Scope and Application」では、Part11においてもすべての電子記録に一様に対応するのではなく、リスクベースアプローチをとることを推奨し、次のように記述している。
「FDA が推奨するアプローチは、リスク・アセスメントの正当化および文書化、そして製品の品質と安全性、記録の完全性に影響を及ぼす可能性をもつシステム判断することに重点をおいたアプローチである。」
またGAMP 5もFDAおよびICH Q9との整合を図るため、リスクベースアプローチを採用している。そのため副題を「 A Risk-Based Approach to Compliant GxP Computerized Systems」とした。ちなみにGAMP 5では、データの完全性、製品の品質、患者の安全に大きく影響するコンピュータ化されたシステムにフォーカスしている。
ERESガイドラインでは、リスクベースアプローチに関しての記載はない。これは対象範囲を資料及び原資料等としており、電子記録全般に及ばないことからであると理解する。
7.4 電子記録に対する要件
ERESガイドラインでは「3.1. 電磁的記録の管理方法」において「真正性」「見読性」「保存性」の3つの要件を求めており、また加えて「3.3. オープン・システムの利用」において「機密性」を要求している。
これに対してPart11では、§11.10 Controls for closed systemsにおいて「真正性および完全性、さらに該当する場合には機密性」を要求している。（図7参照）
さらに§11.10 (b)では「見読性」、§11.10 (c)では「検索性」を求めている。
上記を比較した場合、ERESガイドラインでは、クローズ・システムにおける「機密性」の要求がない。
また「検索性」に関しては記述が見当たらない。
| §11.10 Controls for closed systems 「Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. （電子記録を作成し、変更し、保存し、伝達するためにクローズド・システムを使用する者は、電子記録の真正性および完全性、さらに該当する場合には機密性も含めてこれらが保証されるように、また署名者が署名した記録が真正のものでないと否認することが容易にできないようにするために考案された手続きと管理方法を併用しなければならない。） |
図7 Part11におけるクローズド・システムの利用
7.5 治験における詳細な要件
FDAは、2007年5月に「Guidance for Industry － Computerized Systems Used in Clinical Investigations」と題したガイダンスを発行した。これは1999 年 4 月に発表した「Guidance for Industry － Computerized Systems Used in Clinical Trials」を置き換えるものである。
またこのガイダンスにおいてFDAは「Guidance for Industry － Part11, Electronic Records; Electronic Signatures Scope and Applicationを補足し、臨床試験の現場において発生するソース・データに適用する際の規制当局の国際的調和への貢献の補足となる。」としている。
またEMEAにおいても、2007年11月にGCP IWG（査察検討グループ）が「Draft Reflection Paper on Expectations for Electronic Source Documents used in Clinical Trials（治験で使用する電子的ソース・ドキュメントに関する期待についてのリフレクション・ペーパ（案））」を発表した。
ちなみにリフレクション・ペーパとは、関連する文献等を研究・集積し、自らの考えを述べた文献のことである。
日本の当局は、これら欧米のガイダンスに相当し、ERESガイドラインを補足する治験におけるコンピュータシステムの利用に関する指針を発行していない。
8. 電磁的記録利用システムの2つのタイプ
厚生労働省令第44号の第6条（電磁的記録による作成）には、以下のように記載されている。
「当該書面に係る電磁的記録の作成を行う場合は、民間事業者等の使用に係る電子計算機に備えられたファイルに記録する方法又は磁気ディスク等をもって調製する方法により作成を行わなければならない。」
厚生労働省令第44号が記述している「ファイルに記録する方法」と「磁気ディスク等をもって調製する方法」の区別は、ERESガイドラインには見当たらない。
この電磁的記録の作成の2つの方法は、それぞれ真正性を確保する方法が異なる。
詳しくは本シリーズ第4回を参照されたい。
9. 本格的な査察実施のタイミングと内容
FDAは、1999年5月にCompliance Policy Guide 7153.17（以下、CPG 7153.17）を発表した。
CPG 7153.17は、Part 11に対するFDAの考え方を示し、査察や是正措置執行に際する手引きとなるものである。
このようにFDAでは具体的に査察の考え方を明らかにしている。
日本において規制当局がいつ本格的な査察を行うのか、またその内容がどんなものになるのかは多くの製薬企業の関心のあるところであろう。
なお現在CPG 7153.17は、Part11の改定作業に伴い取り下げられている。
10. おわりに
米国ではPart11発行後、コンプライアンスコストが問題となった。日本においても過剰な投資は避けなければならない。しかしながら電磁的記録および電子署名の信頼性の確保を行うための最低限の対応は必要である。
紙媒体での記録や記名・捺印または手書き署名にかえて、電磁的記録および電子署名を利用したことによって、社会的な混乱を起こしてはならない。
製薬業界に限らず、ずさんな管理による品質の問題により世間を騒がせる事件は後を絶たない。
また規制当局も不作為では困る。IT化の波が押し寄せる現代にあって、業界の電磁的記録および電子署名に関する品質水準を向上させるためのより具体的な指針が望まれる。
参考
- 「PHARMSTAGE Vol.8, No.1 2008 ER/ES実践講座 (第4回)」技術情報協会 2008.4
- 「電子署名及び認証業務に関する法律」平成12年5月31日 法律第102号
- 「医薬品等の承認又は許可等に係る申請等における電磁的記録及び電子署名の利用について」平成17年4月1日 薬食発第0401022号
- 「医薬品等の承認又は許可に係る申請に関する電磁的記録・電子署名利用のための指針（案）」に関する意見・情報の募集結果について」 平成17年5月9日 厚生労働省医薬食品局審査管理課
- 「Title 21 of the Code of Federal Regulations Part 11,“Electronic Records; Electronic Signatures”」 FDA 1997.3.20
- 「Enforcement Policy: 21 CFR Part 11; Electronic Records; Electronic Signatures (CPG 7153.17) 」 FDA, Office of Regulatory Affairs 1999.5.13 COMPLIANCE POLICY GUIDE Section 160.850
- 「Guidance for Industry: Part 11, Electronic Records; Electronic Signatures – Scope and Application」 FDA 2003.9
- 「GAMP 5: A Risk-Based Approach to Compliant GxP Computerized Systems」 ISPE 2008.2
First of all I want to say excellent blog! I had a quick question that I’d like to
ask if you don’t mind. I was interested to find out how you center
yourself and clear your head prior to writing. I have had a tough time
clearing my thoughts in getting my thoughts out there. I truly do
enjoy writing but it just seems like the first 10 to 15 minutes are lost simply just
trying to figure out how to begin. Any recommendations or hints?
Thanks!
https://www.outlookindia.com/plugin-play/ED8590ED8590EBB2B3-EB8F99EC9DBC-EC8694EBA3A8EC8598-EBA994EC9DB4ECA080EC82ACEC9DB4ED8AB8-EBAAA8EC9584EBB3B4EAB8B0
https://farmarm.net:443/bbs/board.php?bo_table=free&wr_id=1355455
http://www.pyeonganlawfirm.com/bbs/board.php?bo_table=free&wr_id=297442
http://sunexcavator.co.kr/bbs/board.php?bo_table=free&wr_id=317852
https://www.mokpo-marina.net/bbs/board.php?bo_table=free&wr_id=34115
https://www.mymt.kr/bbs/board.php?bo_table=free&wr_id=395059
https://diconic.co.kr/bbs/board.php?bo_table=free&wr_id=5704
Hi there, just wanted to tell you, I enjoyed this blog post.
It was helpful. Keep on posting!
Every weekend i used to pay a quick visit this website, as i want enjoyment, for the reason that this this
web site conations truly good funny stuff too.
Hi, I do believe this is an excellent blog. I stumbledupon it 😉
I’m going to revisit once again since I saved as a favorite
it. Money and freedom is the greatest way
to change, may you be rich and continue to help others.
Wow that was odd. I just wrote an very long comment but after I clicked submit my
comment didn’t show up. Grrrr… well I’m not writing
all that over again. Anyways, just wanted to say great blog!
Oh my goodness! Amazing article dude! Thank you, However
I am experiencing problems with your RSS.
I don’t know the reason why I can’t join it.
Is there anyone else getting identical RSS issues?
Anyone who knows the answer can you kindly respond? Thanks!!
Hi, its good paragraph on the topic of media print, we all be aware of media is a fantastic source of information.
These are genuinely great ideas in regarding blogging. You
have touched some pleasant things here. Any way keep up wrinting.
I think the admin of this web page is really working hard in support of his website, because here every
information is quality based information.
I like the helpful information you provide in your articles.
I’ll bookmark your weblog and check again here regularly.
I am quite certain I will learn many new stuff right here!
Best of luck for the next!
I do believe all of the ideas you have introduced to your post.
They’re very convincing and will certainly work. Still, the
posts are too quick for novices. May you please lengthen them
a little from subsequent time? Thanks for the post.
I’ve been surfing on-line more than three hours
today, yet I by no means found any interesting article like yours.
It is pretty price sufficient for me. In my opinion, if all website
owners and bloggers made excellent content material as you
probably did, the net shall be a lot more useful than ever before.
What a data of un-ambiguity and preserveness of precious
experience on the topic of unpredicted emotions.
Hi there, after reading this amazing article i am too
glad to share my experience here with mates.
What’s up it’s me, I am also visiting this site regularly, this web page is in fact fastidious and the viewers are
in fact sharing pleasant thoughts.
WOW just what I was searching for. Came here by searching for naga169 slot
I know this if off topic but I’m looking into starting my own blog and was curious what all is required to get set
up? I’m assuming having a blog like yours
would cost a pretty penny? I’m not very web smart so I’m not 100% positive.
Any recommendations or advice would be greatly
appreciated. Thank you
What’s Going down i am new to this, I stumbled upon this I’ve discovered It
positively useful and it has helped me out loads. I’m hoping
to contribute & assist different users like its aided me.
Good job.
What’s Happening i’m new to this, I stumbled upon this I
have discovered It positively helpful and it has aided me out loads.
I hope to contribute & aid different users like its aided me.
Great job.
Informative article, just what I was looking for.
Everyone loves what you guys are up too. This kind
of clever work and coverage! Keep up the amazing works guys I’ve added you guys to my own blogroll.
Howdy! I know this is kinda off topic however , I’d figured I’d ask.
Would you be interested in exchanging links or maybe guest
writing a blog post or vice-versa? My blog goes over a lot of the same subjects as
yours and I think we could greatly benefit from each
other. If you might be interested feel free to shoot me an email.
I look forward to hearing from you! Fantastic blog by the way!
You can definitely see your enthusiasm within the work you write.
The world hopes for more passionate writers such as you who are
not afraid to mention how they believe. At all times follow your heart.
Pretty portion of content. I simply stumbled upon your web site and in accession capital to say that I acquire
in fact loved account your blog posts. Anyway I will be subscribing in your augment or even I fulfillment you get entry to persistently fast.
Hi there every one, here every person is sharing these experience, so it’s pleasant to
read this blog, and I used to pay a quick visit this
blog everyday.
I go to see day-to-day some web sites and information sites to read articles or reviews, but
this blog presents quality based writing.
I’d like to thank you for the efforts you have put in writing this site.
I really hope to view the same high-grade blog posts from
you later on as well. In truth, your creative writing
abilities has motivated me to get my own blog now 😉
https://ysbaro.com/bbs/board.php?bo_table=free&wr_id=1060483
What i do not realize is actually how you’re now not actually much more neatly-favored than you might be now.
You’re very intelligent. You know thus significantly relating to this topic, produced me in my opinion consider
it from so many numerous angles. Its like women and men aren’t interested
except it’s something to accomplish with Lady gaga!
Your own stuffs great. All the time take care of it up!
Hi there, yes this paragraph is actually pleasant and
I have learned lot of things from it concerning blogging.
thanks.
Hey there! I’ve been following your site for a while now and finally got the bravery to go ahead and give you a shout out from
Kingwood Texas! Just wanted to tell you keep up the great work!
I’m really enjoying the design and layout of your blog.
It’s a very easy on the eyes which makes it much more pleasant
for me to come here and visit more often. Did you hire
out a designer to create your theme? Exceptional work!
I visited several web pages but the audio feature for audio songs existing at
this web site is really excellent.
Good day! I know this is kinda off topic however ,
I’d figured I’d ask. Would you be interested in trading links or maybe
guest authoring a blog article or vice-versa?
My website covers a lot of the same topics as yours
and I think we could greatly benefit from each other. If you’re interested feel free
to shoot me an e-mail. I look forward to hearing from you!
Awesome blog by the way!
I pay a visit every day a few web pages and blogs to read articles or reviews,
except this blog provides quality based writing.
This is my first time go to see at here and i
am in fact happy to read all at one place.
I love your blog.. very nice colors & theme.
Did you design this website yourself or did you hire someone to do it
for you? Plz reply as I’m looking to create my own blog and
would like to find out where u got this from.
many thanks
If you want to grow your know-how only keep visiting this web
page and be updated with the most recent information posted
here.
Your style is unique compared to other folks I have read stuff from.
Thanks for posting when you have the opportunity,
Guess I will just book mark this web site.
What’s up i am kavin, its my first time to commenting anyplace, when i read this piece of writing i thought i could also make comment due to this
sensible piece of writing.
Good day! I just wish to give you a big thumbs up for the great info you have right here on this post.
I am returning to your website for more soon.
I just like the helpful information you
supply to your articles. I’ll bookmark your weblog and test again right here frequently.
I am rather certain I will learn many new stuff right here!
Best of luck for the next!
Now I am going away to do my breakfast, afterward having my
breakfast coming again to read additional news.
It is appropriate time to make some plans for the future and it is time to be happy.
I’ve read this post and if I could I wish to suggest you
few interesting things or tips. Perhaps you could
write next articles referring to this article. I wish to read even more things
about it!
Great delivery. Outstanding arguments. Keep up the great work.
Hello there, I discovered your web site by means of Google while looking for a comparable matter, your website got here up,
it appears to be like good. I’ve bookmarked it in my google
bookmarks.
Hello there, simply become alert to your blog through Google,
and found that it is truly informative. I’m going to be careful for brussels.
I’ll be grateful in case you proceed this in future.
Numerous people will likely be benefited out
of your writing. Cheers!
I am really delighted to read this website posts which includes tons of
valuable data, thanks for providing these information.
I really like looking through an article that will make
people think. Also, thank you for permitting me to comment!
When someone writes an piece of writing he/she retains the image of a user in his/her mind that how a user can understand it.
Thus that’s why this piece of writing is perfect. Thanks!
What’s up everyone, it’s my first pay a quick visit at
this web page, and post is really fruitful in support of me, keep
up posting these articles.
Thanks for finally talking about > ER/ES実践講座（第7回） ERESガイドライン対応のための課題と問題点（その2） | お役立ち情報 < Loved it!
Everyone loves what you guys are usually up too. This sort of clever work and exposure!
Keep up the fantastic works guys I’ve included you guys to
blogroll.
I like the helpful information you provide in your articles.
I’ll bookmark your blog and check again here regularly. I’m quite certain I will learn many new stuff
right here! Good luck for the next!
Quality articles or reviews is the crucial to interest the visitors
to pay a visit the web page, that’s what this web page is providing.
hey there and thank you for your info – I have certainly picked
up something new from right here. I did however expertise several technical points
using this web site, as I experienced to reload the website a lot of times previous to I could get it to load
properly. I had been wondering if your web hosting is OK?
Not that I am complaining, but sluggish loading instances times will
often affect your placement in google and could damage your high-quality score if advertising and marketing with
Adwords. Well I am adding this RSS to my email
and can look out for much more of your respective intriguing content.
Make sure you update this again very soon.
It’s in point of fact a great and helpful piece of info.
I am glad that you shared this helpful information with us.
Please stay us informed like this. Thanks for sharing.
Everything is very open with a really clear explanation of the
challenges. It was truly informative. Your website is very helpful.
Thanks for sharing!
It’s great that you are getting thoughts from this
post as well as from our argument made here.
Hey! Do you know if they make any plugins to assist with SEO?
I’m trying to get my blog to rank for some targeted keywords
but I’m not seeing very good gains. If you know of any please share.
Thank you!
I really love your blog.. Very nice colors & theme.
Did you develop this website yourself? Please reply back as I’m attempting
to create my very own site and want to know
where you got this from or exactly what the theme is named.
Many thanks!
Truly when someone doesn’t be aware of after that its up to other visitors that they
will assist, so here it takes place.
If you want to grow your experience only keep visiting this web site and be
updated with the most recent news update posted here.
I think that what you typed was actually very reasonable.
However, consider this, what if you were to write a killer
headline? I ain’t suggesting your information is not solid., however suppose you added a post
title to possibly get a person’s attention? I mean ER/ES実践講座（第7回） ERESガイドライン対応のための課題と問題点（その2） | お役立ち情報 is kinda plain. You ought to look at Yahoo’s front page and see how they create news titles to grab viewers to open the links.
You might try adding a video or a pic or two to grab readers interested about everything’ve written. In my opinion, it could
bring your posts a little bit more interesting.
of course like your web-site but you have to test the spelling on quite
a few of your posts. Many of them are rife with spelling problems and
I to find it very troublesome to inform the reality then again I’ll
surely come back again.
I every time emailed this blog post page to all my contacts, for
the reason that if like to read it after that my contacts will
too.
Hello Dear, are you truly visiting this website regularly, if so afterward
you will definitely obtain nice knowledge.
I don’t even know the way I stopped up right here, however I thought this put up was once great.
I do not understand who you might be but certainly you’re going
to a famous blogger if you aren’t already.
Cheers!
Have you ever considered about including a little bit more than just your articles?
I mean, what you say is fundamental and everything.
However imagine if you added some great visuals or videos to
give your posts more, “pop”! Your content is excellent
but with pics and video clips, this website could undeniably be one of the greatest in its
field. Great blog!
Good article! We are linking to this great post on our website.
Keep up the good writing.
What’s Going down i am new to this, I stumbled upon this
I’ve discovered It absolutely useful and it has helped me out loads.
I’m hoping to give a contribution & aid different users like
its helped me. Great job.
Hi everybody, here every one is sharing these familiarity, therefore it’s fastidious to read this webpage,
and I used to pay a quick visit this weblog daily.
I must thank you for the efforts you’ve put in penning this blog.
I really hope to check out the same high-grade blog posts from you
in the future as well. In truth, your creative writing abilities has motivated me to get my very own blog
now 😉
Hi there Dear, are you truly visiting this site regularly, if so after that
you will without doubt obtain fastidious experience.
If some one wishes to be updated with latest technologies therefore he must be
visit this web page and be up to date every day.
I have been browsing online more than 2 hours today, yet I never found any interesting article like yours.
It is pretty worth enough for me. In my opinion, if all website owners and bloggers made good content as
you did, the internet will be a lot more useful than ever before.
https://danangplay.com/bbs/board.php?bo_table=free&wr_id=574670
http://whorseland.com/bbs/board.php?bo_table=free&wr_id=20895
https://rentry.co/k3m6po8n
In reality, the ideal game will be the a single you enjoy playing the most.
Feeel free to visit my blog: 카지노친구
We could live iin an age of advancing technology
but some points stay the exact same.
my web-site … 카지노친구
Hey! Do you know if they make any plugins to assist with Search Engine Optimization? I’m trying to get my blog to
rank for some targeted keywords but I’m not seeing very good success.
If you know of any please share. Many thanks!
I saw similar blog here: Eco blankets
This helps to inform and remind attendees of their obligations and the expected conduct in the course of the occasion.
sugar defender official website Discovering Sugar Protector has been a game-changer for me,
as I’ve constantly been vigilant concerning managing my
blood sugar degrees. With this supplement, I feel equipped to take charge of my health
and wellness, and my latest medical examinations have shown a significant turnaround.
Having a trustworthy ally in my edge gives me with a sense of security and reassurance, and I’m deeply happy for the extensive difference Sugar Protector has made in my wellness.
Wonderful post! We will be linking to this great post on our site. Keep up the great writing.
There is definately a great deal to know about this topic. I love all the points you have made.
Right here is the right website for anybody who really wants to find out about this topic. You know so much its almost tough to argue with you (not that I actually will need to…HaHa). You definitely put a fresh spin on a subject that has been written about for many years. Wonderful stuff, just excellent.
Oh my goodness! Impressive article dude! Thank you, However I am experiencing issues with your RSS. I don’t understand why I am unable to subscribe to it. Is there anyone else having similar RSS issues? Anybody who knows the solution can you kindly respond? Thanx!
It has been round without end (in tech time, more than 10 years is forever) and has revolutionized music listening and music shopping for.
bookmarked!!, I really like your blog.
The Robertson Funeral Residence is in charge of arrangements.” (Wilbur Register: 8-08-1974)“George Francis Kunz, Jr, was born at Charlestown , Iowa , Aug 24, 1897.
A memorial service was held on Tuesday, Aug 23, on the grounds of the middle.
9. Chubb: With its headquarters in Zurich, Switzerland, Chubb has been providing house insurance coverage since 1882.
This is a topic that is close to my heart… Thank you! Exactly where can I find the contact details for questions?
There’s definately a lot to learn about this subject. I love all the points you have made.
An impressive share! I have just forwarded this onto a coworker who was conducting a little research on this. And he in fact bought me dinner due to the fact that I stumbled upon it for him… lol. So let me reword this…. Thanks for the meal!! But yeah, thanx for spending time to talk about this subject here on your web page.
Having read this I believed it was rather enlightening. I appreciate you spending some time and effort to put this short article together. I once again find myself spending way too much time both reading and leaving comments. But so what, it was still worthwhile.
Very good info. Lucky me I discovered your blog by chance (stumbleupon). I’ve saved as a favorite for later.
Way cool! Some extremely valid points! I appreciate you penning this write-up and also the rest of the website is extremely good.
Howdy! This blog post could not be written any better! Reading through this article reminds me of my previous roommate! He continually kept preaching about this. I will send this article to him. Fairly certain he’s going to have a great read. Thanks for sharing!
I must thank you for the efforts you have put in penning this site. I’m hoping to view the same high-grade content by you later on as well. In fact, your creative writing abilities has encouraged me to get my own site now 😉
Right here is the right blog for everyone who wants to find out about this topic. You know so much its almost tough to argue with you (not that I actually would want to…HaHa). You definitely put a fresh spin on a subject that has been written about for a long time. Wonderful stuff, just excellent.
Your style is so unique in comparison to other folks I’ve read stuff from. Thank you for posting when you have the opportunity, Guess I will just book mark this page.
Greetings! Very helpful advice within this article! It is the little changes that make the biggest changes. Many thanks for sharing!
Good web site you have here.. It’s difficult to find excellent writing like yours these days. I truly appreciate individuals like you! Take care!!
After I originally left a comment I seem to have clicked the -Notify me when new comments are added- checkbox and from now on whenever a comment is added I get four emails with the exact same comment. Is there a way you are able to remove me from that service? Appreciate it.
Good post. I learn something totally new and challenging on websites I stumbleupon everyday. It’s always interesting to read articles from other writers and practice something from their sites.
Hello there! I just wish to give you a huge thumbs up for your excellent information you have got right here on this post. I am coming back to your site for more soon.
Students who are in better physical well being exhibit increased test scores as a result of they have an inclination to miss fewer courses, and have to repeat courses much much less often than those who have persistently poor health.
Good article. I am going through a few of these issues as well..
I blog frequently and I really thank you for your information. Your article has really peaked my interest. I’m going to bookmark your blog and keep checking for new details about once per week. I opted in for your RSS feed too.
After I originally left a comment I appear to have clicked the -Notify me when new comments are added- checkbox and from now on every time a comment is added I recieve 4 emails with the exact same comment. Is there a means you are able to remove me from that service? Many thanks.
I’m amazed, I have to admit. Rarely do I encounter a blog that’s both educative and engaging, and without a doubt, you’ve hit the nail on the head. The problem is something that not enough folks are speaking intelligently about. Now i’m very happy I found this during my hunt for something regarding this.
I enjoy reading an article that will make people think. Also, many thanks for allowing for me to comment.
From this nation birds are misplaced, is it the hunt or the plague.
We are actually selling the coolest octaver ever made, the Octron and Octron3.
Hi, There’s no doubt that your web site could possibly be having web browser compatibility problems. Whenever I take a look at your web site in Safari, it looks fine but when opening in Internet Explorer, it has some overlapping issues. I simply wanted to provide you with a quick heads up! Besides that, excellent site.
That is a very good tip especially to those new to the blogosphere. Short but very precise information… Many thanks for sharing this one. A must read post.
Having read this I thought it was very enlightening. I appreciate you taking the time and effort to put this informative article together. I once again find myself spending way too much time both reading and leaving comments. But so what, it was still worthwhile.
There’s definately a lot to learn about this topic. I really like all of the points you made.
i could only wish that solar panels cost only several hundred dollars, i would love to fill my roof with solar panels”
Next time I read a blog, I hope that it doesn’t disappoint me as much as this one. I mean, Yes, it was my choice to read, nonetheless I really believed you would have something helpful to say. All I hear is a bunch of moaning about something you could fix if you weren’t too busy seeking attention.
Should you notice your French Bulldog pet is placing on a lot weight, you might want to limit his/her meals consumption.
You are so cool! I don’t think I’ve truly read something like that before. So wonderful to discover another person with some original thoughts on this issue. Really.. thanks for starting this up. This website is something that’s needed on the internet, someone with some originality.
An outstanding share! I’ve just forwarded this onto a co-worker who had been doing a little homework on this. And he actually bought me breakfast simply because I found it for him… lol. So allow me to reword this…. Thank YOU for the meal!! But yeah, thanx for spending some time to discuss this subject here on your web page.
I want to to thank you for this fantastic read!! I definitely loved every little bit of it. I’ve got you book marked to look at new things you post…
I really like your writing style, good info , thankyou for putting up : D.
You have a very nice layout for your blog” i want it to use on my site too “
Greetings, There’s no doubt that your web site could be having browser compatibility issues. When I look at your blog in Safari, it looks fine however, if opening in IE, it has some overlapping issues. I just wanted to provide you with a quick heads up! Apart from that, excellent blog.
Howdy! This post could not be written any better! Going through this post reminds me of my previous roommate! He continually kept talking about this. I’ll forward this information to him. Fairly certain he’s going to have a good read. I appreciate you for sharing!
There’s definately a lot to know about this subject. I really like all of the points you have made.
[…]below are some web page links to places which we connect to as we feel they will be well worth browsing[…]
Everyone loves it when people get together and share thoughts. Great blog, continue the good work!
Wonderful job right here. I seriously enjoyed what you had to say. Keep going because you undoubtedly bring a new voice to this subject. Not many people would say what youve said and still make it interesting. Properly, at least Im interested. Cant wait to see far more of this from you.
used trucks are sometimes expensive and it is quite hard to find a good bargain if you don’t search heavily-
Oh my goodness! an incredible article dude. Thanks Nevertheless I am experiencing subject with ur rss . Don’t know why Unable to subscribe to it. Is there anybody getting equivalent rss downside? Anyone who knows kindly respond. Thnkx
Hey. Very nice web site!! Guy .. Excellent .. Wonderful .. I will bookmark your website and take the feeds additionally…I am satisfied to locate numerous useful information right here within the post. Thank you for sharing..
Hello, i think that i saw you visited my weblog so i came to “return the favor”.I’m trying to find things to enhance my site!I suppose its ok to use a few of your ideas!! empire blue cross blueshields
Very good write-up. I absolutely love this site. Stick with it!
There is clearly a lot to know about this. I think you made various good points in features also.
I’d like to thank you for the efforts you have put in penning this website. I really hope to check out the same high-grade blog posts by you in the future as well. In fact, your creative writing abilities has inspired me to get my own site now 😉
I didn’t quite understand this when I first feature it. Merely when I went through it a second time, it all became clear. Thanks for the brainstorm. Absolutely thing to remember just about.
i get my art books from barnes and noble that come or amazon, they have some great discount coupons too”
Aw, this was an exceptionally nice post. Taking a few minutes and actual effort to produce a superb article… but what can I say… I hesitate a lot and never manage to get anything done.
Very nice article. I absolutely love this website. Continue the good work!
I like what you guys are up also. Such smart work and reporting! Keep up the superb works guys I’ve incorporated you guys to my blogroll. I think it will improve the value of my website .
fantastic post, very informative. I’m wondering why the opposite specialists of this sector don’t understand this. You must continue your writing. I am sure, you have a great readers’ base already!
my hard drive is getting full already because i always download free online movies on the internet~
Can I just say what a relief to find someone who really knows what they’re talking about on the net. You actually realize how to bring a problem to light and make it important. More and more people need to check this out and understand this side of your story. I was surprised that you’re not more popular given that you surely possess the gift.
Hello There. I found your blog using msn. This is a really well written article. I will make sure to bookmark it and come back to read more of your useful info. Thanks for the post. I will certainly return.
Thank you for another great article. Where else could anyone get that kind of information in such a perfect way of writing? I have a presentation next week, and I am on the look for such information.
wooden kitchen cabinets are perfect your your home, they look good and can be cleaned easily*