Permit Autograph Template with airSlate SignNow

Permit autograph template

thanks mahaj for the introduction my name is peter q i will be the last presenter for this session i'm currently an acting director in the division of biotechnology manufacturing in the office of pharmaceutical manufacturing assessment by now you have heard of the previous presentation on pre-approval inspections for nds ndas now i'm going to talk about the pre-license inspection for biological products so in my presentation i will cover those four areas the regulatory definition of biological products highlight some uh regulatory requirements for biological products submitted under bla then of course i will talk about the pre-approval pre-license inspection program in cedar i will end with some examples for common deficiencies founded during our application review and our inspections what is a biological product first of all i want to mention that unlike nd a and da's biological products are licensed under the section 351 of public health service act or phs act the phs act also provides a definition of biological product as stated in in this slide i'm not going to read the entire definition but i just want to point out some recent amendments made to the phs act the act was amended this year to include protein as a biological product which is defined as any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size in addition the biologics price competition and innovation act of bpci act of 2009 which also included a deemed to be a licensed product those are biological products that were previously approved under section 505 of the fdnc act on or before march 23 2020. now those parts are deemed as bis you can find more information about those deemed to be a licensed product on the fda's website biological products are regulated at both siebel and the cedar c burba center for biologics cedar center for drugs here i provide a list of prototypes that are regulated by cedar those are include two main areas monoclonal antibodies for in we will use most therapeutic proteins such as interferons enzyme and other novel proteins for therapeutic use but we also regulate immunomoderators and growth factors in cedar what are the requirements for obtaining about a bla license for biological product as stated under 21 cfr 601.4 prior to issue a license that fda must determine that the product the manufacturing process and the manufacturing facility must meet the standards stated in the regulations in addition for ibra the applicant must complete the commercial scale process performance qualification studies or ppq studies and submit the data in the application you can find more information about the requirements for process validation in the in the fds 2011 guidance on process validation which is also available on our website another requirement is each manufacturing facility must be ready for inspection and is manufacturing the product in support of upper licensing expression i'm going to talk more about the pre-licensing expression in later in this in this presentation the last thing i want to point out in this slide is for boas we do not accept application that referencing drug master files or dml files for drug substance drug substance intermediate or drug product with some exceptions for uh those themed to be licensed product again if you want to know more about this you can go to our website to find this information on the requirement for dmf files another area i want to talk about is a aseptic processing as you all know that almost all the biological products are stereo injectables and have to be manufactured using aesthetic processing due to the nature of those products so it is very important to understand the gmp requirements as well as well as a summation requirement for those type of products here i include two very useful fta gardens on aseptic processing the 2004 guidance describes the gmp requirements for aseptic processing according to the 21cfr 210 211 when manufacturing sterile drugs and the biologics using aseptic processing the 1994 guidance describes information required in a boa to support our series assurance so this uh this included identification of the manufacturing areas and the type of feeding lines we need to know that if the product is filled in a isolator wraps open or closed wraps or just a conventional open feeding room which will consider very high risk for potential contamination you also need to provide the information about the surrounding areas classifications for example you have a grade area surrounded by grade b or c areas so those information should be included in the application and also you need to provide the data for uh under sterilization and the departure generation for product contact equipment container called your systems and other components again you provide information on media fields number of batches we usually expect three successful batches of media field data and your investigation for if that positive growth and the procedures for media fuel including interventions you also need to provide the data to demonstrate the integrity of container code your systems and also other method validation data and also release criterias now i'm going to switch to inspections as you know inspection is a critical part of a bi assessment to evaluate the product quality and obtain or observe manufacturing operations under gmps the 600 regulations provide the regulatory authority for our conducting for us to conduct uh pre-licensing inspections 21 cfr 600.21 talks about the timing of inspections inspections should be conducted while the establishment is uh in operation and is manufacturing the completed product 21cfr 601.20 provides the regulatory requirements before issuing a biological license that includes a product examination to determine that they are in compliance with derogatory requirement but that should be available for inspection during all phases of manufacturing and the conducting inspection to determine each facility years in compliance with a regulatory requirement when asset review team evaluates a facility associated with a bla to determine if inspection is required we consider risks in the following areas so first on the facility side we look at the prior inspection history for that facility it is a new facility a new building or a new feeling line without fda inspection history does they have experience with similar manufacturing process for example prior experience with biotech manufacturing and aseptic feeding for drug product are there any information available from other regulatory authorities that covers similar manufacturing operations so we take all of this that all those informations evaluate that facility we also look at gmp issues if they are relevant to this product so this means we will assess previous observations to see if there are any relevance to this application we assess the product risk for example it is a potent or toxic order any concern with our cross-contamination novel technologies for example if the application uses like for the uh conducive manufacturing or single-use technologies those are considered high risk and process capacity so one example is i would say antibody drug conjugate that's a relatively high risk and the application specific concerns uh any issues identified during application review for example data concerns to get the data together to be true that will trigger an inspection and the last part i want to see is that there's any if there's any significant process changes this is mainly for our post-approval changes supplements so in addition to conductor on-site inspections we do have other alternative approaches to on-site inspections this is really based on the holistic assessment of the site and applications you probably have heard the records review in the 70484 of the fdnc act in advance or in law of inspection this is also we also abuse that for bla inspections we also consider uh onsite inspection waivers this again based on the could be based on the records review in law for inspection prior inspection history of this facility and experience of uh with similar manufacturing products are processed at this facility again the decision will be made by the entire cmc rebuilding as part of the holistic assessment of the application in the manufacturing site as a sponsor or applicant how to prepare for a pre-licensing expression first of all we highly recommend that before you submit a boa you engage early communication or discussion with the agency this is really important if the product is under some kind of expedited review program for example breakthrough drugs so we can have early discussion with the sponsor on the manufacturing facilities and the timing of inspections it is also very important to provide the production schedules in the application for i'm talking about for drug substance and drug product manufacturing manufacturing sites you receive the ir from us and please make sure that you provide the timely response so this will help us to plan our inspections you could also consider conducting a market inspections to assess the site's readiness for inspection and also verify the information submitted in your application is complete accurate and consistent with the site records of course the size should be ready for inspection upon summation now i'm going to share with you some common deficiencies we found during application review and also on inspections on the uh submission side uh i just want to mention that some of those deficiencies i'm going to discuss in this slide i also consider filing issues so when one example is uh ppq studies were not complete to support submissions this really include like incomplete pbq studies uh ppq batches failed and in the application that could not demonstrate a consistent manufacturing process as i said before that usually we expect three successful ppg batches with the data in the application another thing is uh changes were made to the manufacturing facility or the manufacturing process after completion of the ppq studies that puts a question about the immutability of the ppq studies that no production scheduled during the review cycle to support the pre-licensed inspection and then this is a filing issue and the missing data or insufficient data to support uh sterility assurance failed to submit equipment qualification for example uh autograph qualification process simulation media field data was i did not include the three midi field data and the missing testing master validation data another common deficiency deficiency is a discrepancy between the information simulating application and the manufacturing process performed at a site this is a common deficiencies for some cmos so we really want you to make sure that before you submit the application the information is completed in the application is completely accurate and consistent with the site records for inspection deficiencies first i want to talk about quality oversight we have seen some inexperienced cmos or sponsors that don't really understand each party's responsibilities for application analysis inspections for example that the sponsor and the cmo they don't really know who is responsible for investigating deviations oss and or release batches quality units don't really review the computer release data before these batch release they don't look at the audit trails and of course inadequate uh investigation for deviation and os and the kappa uh implementation plans data reliability this is another concern unfortunately that we are seeing more in the biotech areas so we have seen as a manipulating sample preparation and the testing procedures to obtain favorable results we sometimes can't i can identify those issues in the application review this is as we call we call the data too good to be true so if if we find the second incidence during the inspection we will pay extra attention to those datum and to make sure those uh the data is completely accurate we're seeing a deletion of electronic data including audit trails whether it is intentionally or unintentionally done operators were given a admin privileges so they can access data files to delete the data even the computer files aseptic processing deviations observing the aseptic operation is a major activity for our pre-licensing inspection at the drug product side so here i share with you some common deficiency deficiencies we observed over the years one year's uh one example here the smoke studies so by now we're hoping that most manufactured manufacturing sites should already know what should be covered in a smoke studies however we still see seeing a lot of critical deficiencies in the smoke studies for example that smoke study only covered the static conditions missing a setup activities no simulation for dynamic conditions no interventions and this is especially important of the feeding operation here the open feeling with a lot a lot of interventions media field does not simulate the entire manufacturing operations so one example here as you know during routine productions often the manufacturing process is designed to include a final purge step to push the product out of the vessel or tubing to minimize product loss however during media field this is generally not a concern so i have seen here the media program midi field programs designed to skip the final purge step so in other words the purge step is never simulated in a media field this is a major issue in adequate environmental monitoring for example there's no em during uh feeling like setups in other inadequate aseptic process practice uh excessive excessive movement during the filling operations in graph disinfection prior to touching steroid product contact equipment in summary as i present here there are some bra specific regulatory requirements with regard to data submitted in an application and there are inspections so for example commercial scale ppq studies have to be completed and the data submitted in the application products should be available for examination and inspection during all phases of manufacturing in general a pre-license or pre-approving spending is required for a bra and certain supplements for us to evaluate the product quality and observe manufacturing process processing to verify compliance with commitments made in the applications and also to meet the gnp requirements here is my contact information if you have any questions please feel free to contact me so this uh concludes my talk and the first session we will take a brief break so we can take a look at your questions and we'll be back to answer your questions thanks