Regulatory Education for Industry (REdI) Annual Conference 2023 Day 2 Session 4 and Closing

welcome back from the break we're on the home stretch now our first presentation and our final session is on the best practices for human drug product recalls our presenter Doris Chen is a consumer safety officer in the incidents recall and shortages Branch division of supply chain Security Office of drug security integrity and response and the office of compliance next we'll present a Rough Guide to biologics

manufacturing our presenters include Dr Joel Welch who's the associate director for Science and biosimilar strategy and chair for emerging technology team in the office of Technology products and opq and finally in this presentation we welcome Dr Chris Downey who's the director and the division of Biotech manufacturing within the office of pharmaceutical manufacturing assessment in opq please join me to welcome our first presenter Doris Chen thank

you for that introduction and good afternoon again my name is Doris chin and my presentation will be best practices for drug product recalls in the event your firm ever needs to conduct a voluntary recall you'll definitely want to keep a copy of these slides to refer to later additionally I have an extensive references and resources section which you will want to print out so that you

can refer to the most up-to-date guidances recall coordinator contacts and other pertinent information let's discuss our learning objectives completion of this presentation you will know when to conduct a human drug recall who to contact in FDA to report it how to implement your recall and lastly how to evaluate if your recall was effective let me start by sharing with you what the center for drug evaluation

and research or Cedar's office of compliance's mission is and that is to Shield patients from poor quality unsafe and ineffective drugs through proactive compliance strategies and risk-based enforcement action that's a lot of words but it means that here in the office of compliance we want to protect the public from violative drugs by encouraging The Firm to do the right thing by taking a market action to

remove their violative drug product or by using some of our compliance or enforcement tools like seizure of products warning letters or if the product was imported from outside the U.S an import alert that prevents new product from coming into the U.S market I work in the office of drug security integrity and response our office has many component branches I work specifically in the incidence recalls and

shortages branch on the recalls and shortages team our goal is to facilitate proactive risk-based Regulatory Compliance actions based on science and the law in a timely and efficient manner in order to protect the drug supply chain Integrity we aim to provide high quality services and to promote excellence and collaboration in our Partnerships with all stakeholders our incidence team coordinates response to incidents and informants that threaten

the safety and quality of the nation's drug Supply involving counterfeits unapproved drugs and Manufacturing quality issues and collaborates closely with other agency resources to resolve these Public Health threats are recalls and shortages team classifies recalls of all human drug products regulated by Cedar we process recall recommendations through Cedar recall referrals which we'll touch on later we coordinate potential and initiated recall activities by engaging with all

relevant agency units including field divisions in the office of Regulatory Affairs we obtain technical evaluations on compounding related issues from the office of compounding quality and compliance adulteration issues from the office of manufacturing quality and this branding violations from the office of unapproved drugs and labeling compliance our team acts as the point of contact for and supports the drug shortages staff by coordinating all Cedar office

of compliance program actions for management of human drug shortages we conduct compliance shortage evaluations related to firms that may be impacted by recommendations of enforcement actions such as warning letters or import alerts we coordinate the office of compliance evaluation of shortage proposals from industry sent to the drug shortages staff we obtain and evaluate Cedar health hazard evaluations which are obtained for classification of recalls or for

potential regulatory actions how do you know if your firm needs to conduct a recall a recall can be initiated at various levels of the drug supply chain it could include manufacturers contract manufacturers Distributors own label distributors or wholesalers just to name a few a recall can also include excipients active pharmaceutical ingredients or components a recall does not have to only be a finished drug product let's

start by defining what is a recall referring to 21 CFR 7.3 g a recall is a firm's removal or correction of a marketed product that the Food and Drug Administration considers to be in violation of the laws it administers and against which the agency would initiate illegal action such as a seizure a recall does not include a market withdrawal or a stock recovery so a recall

is for a violative product that has been distributed outside the firm's control a market withdrawal is a firm's removal or correction of a distributed product which involves a minor violation that would not be the subject of a legal action by the FDA or which involves no violation what do you consider before you conduct a recall you're not sure a recall is necessary your product is approaching

expiry and is not expected to meet specification at expiry should you recall if you have a product you believe is violative be transparent reach out to your Ora Farm point of contact and discuss the situation Ora form can provide guidance if your Market action fits the definition of a recall you're concerned about a drug shortage if you believe a market action would cause or exacerbate a

shortage of a medically necessary product reach out with your proposal to Cedar's drug shortage staff before initiating a recall the drug shortages staff will review your proposal and determine if this is a viable option to keep an otherwise violative product on the market because the benefit of having the product on the market outweighs the risks as I mentioned before our recalls and shortages team will coordinate

with offices within Cedar's office of compliance and the drug shortage of staff to evaluate the situation taking into account mitigating factors that will allow the safe use of a product that is otherwise violative shortage notifications and updates may be reported to FDA at drug shortages at fda.hhs.gov we also have guidance for notifying FDA of a permanent discontinuation or interruption in manufacturing under Section 506 C of

the food drug and cosmetic act so if you're aware of issues that could lead to permanent discontinuation of a product or could temporarily cease manufacturing or release you must notify the FDA prior to those actions so whether you're in a situation where you're considering a recall or not you want to be prepared make sure that you establish and maintain recall Sops in accordance with the FDA

guidance and regulations you can find many of these resources on my references and resource pages so that you know what to do when you're ready to recall identify and train your staff on those procedures establish recall communication plans so that you know how you will notify your companies that you're recalling know your FDA recall tools and contacts what do you think has been the number one

reason for recalls in the past three years is it a failed to solution specifications B lack of sterility assurance C subpotent drug D failed impurities degradation specifications or e current good manufacturing practices deviations how did everyone do the number one reason for recalls over the past three fiscal years has been e c g m p deviations now let's look at the data for fiscal year 2020

2021 and 2022. the top reasons for human drug recalls have been a combination of cgmp deviations failed impurities degradation specifications a lack of sterility Assurance subpotent drug and failed dissolution specifications with the number one reason being cgmp deviations as appropriate your firm should Implement procedures to identify indicators that there may be a problem with a distributed product that suggests it's in violation of the food drug

and cosmetic dact and other laws administered by FDA examples of indicators may include an internal report of a product specification deviation or add a specification testing results for our product consumer complaints about a product this could include reports of Adverse Events reports of disease injury or death associated with product use or inspectional observations related to a product made by a regulatory Authority and indicating non-compliance with

applicable product regulations think is the most common form of initiation for human drug recalls is it a firm initiated B FDA recommended C FDA requested or D FDA mandated how did everyone do the answer is a firm initiated let's talk about the different ways recalls can be initiated firm initiated are ones where the firm on its own may decide to voluntarily recall and Report their action

to FDA FDA recommended are ones where Ora Farm will coordinate a call with cedar and the firm to recommend a firm voluntarily recall due to information supporting product adulteration and or misbranding charges I mentioned earlier that our team processes the recall referral forms that we receive from other offices within Cedar's office of compliance such as the office of manufacturing quality office of unapproved drugs and labeling

compliance and the office of compounding quality and compliance the recall is still considered a voluntary decision by The Firm FDA requested recall is ordinarily reserved for urgent situations where mandatory recall Authority does not exist or is not appropriate most often these are class 1 situations where there's a reasonable probability of a serious adverse event or death associated with use of the violative product and the firm

has not yet recalled on its own the FDA requested recall is a letter from the associate commissioner for Regulatory Affairs to the firm requesting they initiate a recall the recall is still a voluntary decision by The Firm mandatory recalls are for controlled drug substances only at this time where there's a reasonable probability of serious adverse Health consequences now let's talk about what to consider when reporting

your recall to FDA this can include who should I contact at FDA what if FDA contacts me to recommend a recall what information should I provide who do you contact at FDA to initiate your recall the office of Regulatory Affairs recall coordinators are your primary points of contact for recalls I've also included a link for the FDA Ora recall coordinators in the references and resources section

the USA and its territories are divided into four divisions and you will work with the division based on your geographical location to discuss a potential Market action or to implement your recall if your firm is located outside the U.S and you distribute within the USA your U.S agent will act as your representative and facilitate your recall on your behalf your U.S agent will contact the Ora

recall coordinator based on their geographical location the Ora Pharma recall coordinators can provide information on initiating and conducting your recall and provide guidance through all the steps up to terminating your recall what should you do if FDA contacts you first if FDA contacts you this would be considered an FDA recommended recall Cedar recalls typically coordinates with Ora Farm to recommend a voluntary recall based on findings

supporting product adulteration and or misbranding charges during this call we will communicate to a firm the recommended products issues charges and recall initiation guidance this is followed up with written guidance from the Ora Farm recall coordinator and we recommend a 24-hour response from the firm in writing with the firm's decision when you have made the decision to voluntarily recall your product or products what information do

you provide to FDA this information is summarized in something called attachment B you can refer to the link for the regulatory procedures manual chapter 7 that provides FDA guidance on what information you would include such as product information strength package size UPC or NDC codes lot information copies of labeling firm information for the recalling firm manufacturing firm and the responsible firm who caused the recall the

reason for your recall and your health hazard evaluation or assessment volume of recalled product its distribution and constantly list and your proposed recall strategy including copies of recall letters and press release if one was issued things do you consider when you're ready to implement your recall how do you determine the appropriate scope and depth what level of recall communication is appropriate in order to answer those

questions we first need to understand the three recall locations which are determined by the recalls and shortages team I want you to understand the classifications however FDA determines the classification and not the firm class one is a situation where there is a reasonable probability that use of or exposure to a violative product will cause serious adverse Health consequences or death Class 2 is a situation where

you sell or exposure to a violative product may cause temporary or medically reversible adverse Health consequences or the probability of serious adverse Health consequences is remote class 3 is a situation in which use of or exposure to a violative product is not likely to cause adverse Health consequences your recall strategy is a plan specific course of action to be taken in conducting a specific recall which

addresses the depth of the recall need for public warnings and extent of Effectiveness checks for the recall let's talk about the depth of a recall depending on the product's degree of health hazard its likelihood for occurrence and extent of distribution the recall strategy will specify the level in the distribution chain to which the recall is to extend to in Cedar we typically will recommend wholesale retail

pharmacy or consumer user level depths scope is the recalled lots that are or may be affected FDA will want to know your bracketing rationale for limiting your scope to the recalled Lots identified FDA will also want to know your bracketing rationale in the event you made the decision to expand the scope of the recalls include additional Lots upon review of your scope response among other information

there may be circumstances where FDA recommends an expansion beyond what you're recalling your firm's recall Communications are based on the product defect risk and is determined as part of your recall strategy see the resources and references slide for links to the regulatory procedures manual where you can find model recall letters and response forms as well as a model press release should you wish to include press

as part of your recall strategy press is recommended for high risk recalls which would include potential class 1 recalls or recalls to a vulnerable population such as over-the-counter infant or children pain reliever products the firm's recall press release is posted on fda.gov's website after drafting your press release using the press release template you would work with your Ora form recall coordinator who will send it for

review and let you know the agency's comments and edits before you post it let's talk about some FDA recall Communications and what they are alert warns consumers not to use a certain product it is generally issued when the firm has not yet taken a market action or the firm's communication is inadequate and Cedar needs to clarify Peter immediate public notification is technically not a recall Communication

in itself however it is generally initiated by Health fraud when FDA analysis has found a tainted dietary supplement and wants to warn consumers not to use them this is different than the recall Cedar alert because the manufacturer or Distributors are unknown or often difficult to find an FDA press release is an agency level communication to get the attention of the media and helps amplify the agency's

message to patients this is usually reserved for serious defects for example those that can result in death the FDA enforcement report contains recalls that have been classified or have been posted as determined to fit the definition of a recall but are not yet classified evaluates the effectiveness of a recall by evaluating a company's efforts to properly notify customers and remove the defective product from the market

if a recall is determined to be ineffective FDA will request the company take additional actions Effectiveness checks verify that all consones at the recall level depth specified by your strategy have received notification about the recall and have taken appropriate action it's fda's expectation that you reach out to a hundred percent of the consonants that you sold or distributed your recalled product to in order to ensure

your recall was effective you will conduct Effectiveness checks refer to the guidance for industry for model Effectiveness check letters and response forms communicate regularly with your consonants to ensure they receive their recall letter and understand what to do follow up with constantees that have not been responsive before Ora form will terminate your recall all reasonable efforts shall be made to remove the violative product from the

market therefore communicate with your Ora Farm recall coordinator contact to keep them apprised of the status let's talk about a few high-profile recalls we have seen in the news recently contaminated ophthalmic products and hand sanitizers as I discussed the case studies what indicators do You observe and if your firm manufactures sterile ophthalmic products or hand sanitizers what best practices can you take back to your team

this is a screenshot of the CDC webpage CDC alerted the FDA of an outbreak of a drug resistance pseudomonas originosa strain associated with the use of an over-the-counter artificial tears product CDC have tested products found a commonality with one drug manufacturer based on concerns with contaminated products that already entered the market and Manufacturing information provided by The Firm Cedar recalls an RA form contacted the firm

and recommended a recall the firm agreed to recall all distributed Lots the Distributing firms who are the recoing firm's consones were to conduct a sub recall which is an action taken to notify their own consonants of the recall as long as a recalled product is unchanged including the packaging if you are a manufacturer of ophthalmic drug products what best practices did you learn from this presentation

under 21 CFR 200.50 all ophthalmic drug products must be sterile review your manufacturing process is it adequate for sterile production review your formulations in container closure systems is your product a single used product without a preservative is your product a multi-dose product does it have appropriate controls to prevent microbial growth throughout its shelf life ensure your products are manufactured under cgmps if you are aware there's

a problem quarantine the products and stop distribution while you're deciding on an action and keep the agency informed since the beginning of the pandemic we have seen an increase in hand sanitizer products come on the market some imported into the USA because domestic resources could not keep up with the demand firms saw a need and possibly a monetary incentive for marketing hand sanitizers the problem was

that some of these products had the presence of methanol one propanol acetal or acetaldehyde some were either subpotent or super potent for ethanol some had microbial contamination some were packaged in food type containers like the pouches they sell pureed fruit in for children or bottles resembling water bottles some products were even labeled as being edible as of May 1st 2023 the agency recommended 104 voluntary recalls

from firms who manufactured or distributed violative hand sanitizer products and 150 violative hand sanitizer products have been recalled the FDA used additional regulatory tools to protect the U.S public that include firm-based and a country-based import alert on the fda.gov website you can see a full list of hand sanitizers that the agency urges consumers not to use for a manufacturer of hand sanitizers what best practices did

you learn from this presentation know your suppliers like the API components supply chain are they reputable ensure your products are manufactured under cgmps if you're aware there's a problem quarantine the products while you're deciding on an action keep the agency informed if the agency is letting industry know there is a problem look into the issue to see if it impacts your product these best practices are

also true for other types of drug products not just hand sanitizers ready for our first challenge question which of the following ways of initiating a recall is not considered voluntary is it a firm initiated B FDA recommended C FDA requested or D FDA mandated the answer is D FDA mandated firm initiated FDA recommended an FDA requested are still considered voluntary actions challenge question two if I

have a product that I'm not sure if I should recall I should a contact my local Ora Farm recall coordinator to obtain guidance B wait until I'm inspected and let the investigators ask me why I didn't take a market action C do nothing and hope for the best D wait until there are Adverse Events reported I hope everybody got this the answer is a contact my

local Ora Farm recall coordinator to obtain guidance challenge question three which of these scenarios is not considered a recall a distributed product that failed in Purity specifications B product lot that attained out of specification results for dissolution but is now expired see lots that were tested that meet specification but are supported by a stability lot that failed for assay D liquid product that was manufactured using

water that was found to be contaminated but finished product testing did not find contamination the answer is B a product may be oos but at the time you initiate the recall it cannot be expired you can recall product on the day it expires as long as you notify your consones regarding the recall before the x-free date here are some closing thoughts conduct effective recalls in the

interest of Public Health established adequate recall procedures that support early imprompt execution of appropriate Market action by well-trained staff know your FDA contacts and important tools such as FDA guidance and websites recalls procedures manual and the code of federal regulations also known as the CFR and talk to FDA early and transparently take these four major points back to your team and make sure your firm will

be prepared in the event you ever need to recall thank you the four resource slides I spoke about in my presentation are in the PDF file of this presentation that you can download with my slides from the website these will be helpful for you to print out and refer to should you ever need to recall I will be back shortly for our q a session thank

you good afternoon it is a real pleasure to be with you today my name is Joel Welch and I am the associate director for Science and biosimilar strategy in the office of biotechnology products in the office of pharmaceutical quality in Cedar my co-presenter today is Dr Christopher Downey who is the director for the division of biotechnology Manufacturing in the office of pharmaceutical manufacturing Assessments in the

office of pharmaceutical quality and Cedar before we begin our presentation we first must begin with a foundational idea which is what is the meaning of pharmaceutical quality everyone deserves confidence in our next dose of medicine and pharmaceutical quality assures the availability safety and efficacy of every dose this presentation will include a basic background on how biological products such as monoclonal antibodies and other therapeutic proteins are

regulated by FDA Cedar it will discuss unique factors for chemistry manufacturing and controls for biological products including both scientific and Regulatory nuances the presentation will also address how Cedar approaches inspectional activities for these biological products and finally it will identify key themes common that lead to complete responses for marketing applications for these products first I will Begin by discussing some of the unique factors of chemistry

manufacturing and controls for biological products including both their scientific and Regulatory nuances for these programs before we begin it's helpful to clarify which Center regulates which biological product the center for drug evaluation and research regulates monoclonal antibodies for in Vivo use and most proteins intended for therapeutic use for example enzymes or cytokines the center for biologics evaluation and research regulates other biological products this would include

cellular products Gene therapies vaccines and vaccine Associated products regardless of their structural composition allergenics blood and blood components and finally human cell and cell and tissue based products with regard to biological products regulated by Cedar described in the previous slide this summary helps identify the type of application that would be submitted for our potential product to Cedar as you can see the dividing line between new

drug and biologic is 40 amino acids for products 40 new acids or fewer they're regulated as new drug applications or subsequently abbreviated new drug applications for products greater than 40 amino acids a biological license application is submitted critically this is true even for molecules for which the amino acid polymer is made by chemical synthesis or derived from a biological Source material including production through competent technology

this slide attempts to summarize steps associated with a typical manufacturing process for a recombinant protein therapeutic it summarizes Key activities grouped by their scientific function and on the right the guidances associated from ich the International Conference on harmonization you can see the guidances are grouped on the particular topic of the Technology and Manufacturing process portion they support process begins with the creation of an expression system

using a desired Gene an expression Vector to create a cell to populate the cell substrate and with it create an expression system from there cell banking establishes how typical production will be performed after cell banking cell culture begins to generate protein which is subsequently harvested and purified and becomes what we call the drug substance formulation and fill finish then is performed and results in the final

drug product to be given to patients some guidances apply only to a subsection of these activities while some like Q7 apply to the whole drug substance finally overarching guidances such as m4q on dossiery Arrangement and q9 Q10 q12 which describe quality risk management pharmaceutical Quality Systems and finally Technical and Regulatory consideration for the life cycle respectively would apply to the entire process nevertheless in the addition

to the regulatory considerations biological products will have some very specific unique scientific considerations that need to be addressed as well first biological products are frequently highly complex in both their size and number of cqas critical quality attributes relative to small molecule products secondly biological products frequently have not only product related impurities but also product related substances that may retain activity which drives both the need for

consideration of molecular molecular characterization as well as that molecule's control this control strategy May well be informed by methods and data generated not only at the intended commercial process and scale but frequently generated in scale down models which are needed to evaluate some aspects of a manufacturing process that cannot be performed at scale such as viral clearance understanding how a model was qualified and its relationship

to commercial manufacturing is a key feature this control strategy for critical quality attributes May well be informed by some techniques that may not fully resolve each quality attribute such as the charge variant profile shown here on the bottom right of the slide understanding the totality of how an attribute is monitored and controlled is therefore critical finally these critical quality attributes may not only be molecule specific

that may well be indication specific as well such as an effector function for a monoclonal antibody depicted here on the bottom left which might demonstrate antibody dependent cellular cytotoxicity and only a subset of indications here we discuss the role of process validation and the expectations for biologics the process validation is fundamentally the collection and evaluation of data which establishes scientific evidence that a process is capable

of consistently delivering a quality product it is a series of activities that occurs over the life cycle of the product and process process validation is divided into three stages stage one is process design where experience helps Define the manufacturing process stage two includes an evaluation of the capability of the process and finally stage three continued process verification demonstrate that the process remains in a state of

control the validated State during the commercial manufacturing lifetime process validation stage 2 or what is sometimes referred to as PPQ or process performance qualification is a potential distinction between and as and ndas and biologic license applications while PPQ must be completed prior to commercial distribution for all molecules this data is expected to be submitted in the dossier for assessment at the time of bla submission additionally

for Blas the facility should also be manufacturing the product for list licensure is sought during the review as well biologic license applications have unique considerations and conditions that must be met as a part of their licensure first the facility in which the biological product is manufactured processed packed or held must meet applicable standards as mentioned previously inspection plays a critical role for biological products and this

is a topic that will be discussed in Greater detail by Dr Downey for this reason additional considerations such as consent to inspection and a determination that the product complies with license conditions and meets applicable standards must also be performed critically these licensing conditions apply equally whether or not you are submitting a 351a or 351 K application given the unique consideration for Blas that have just been

discussed several other key items should be considered when preparing a submission first it is important to make sure all facilities are registered with FDA at the time of inspection secondly a preliminary manufacturing schedule should be provided in the dla submission to facilitate the planning of pre-licensure inspections during the review cycle for this reason manufacturing facilities should be in operation and Manufacturing the product unreviewed during the

inspection finally as the FDA expects that a licensed holder has knowledge of the control over the manufacturing process of the biological product for which it has license for which it seeks licensure type 2 dmfs for drug substance direct substance intermediate and direct product are not typically permissible for bias for biological components finally key data and information should be included to ensure sufficient information is provided to

describe both routine operation and data commitments that are ongoing as part of the biologics license application provided here is a list that is not comprehensive but gives some of these critical examples these include data to support shipping validation and information on the ReUse of key materials such as membranes and chromatographic purification resins in addition routine monitoring for things such as reference standards and cell Bank should

be provided with specifics on how they will be monitored finally other elements while not required are also potential nice to have submission elements these could not include qualification protocols for things such as new reference standards or new cell Banks this brings us the challenge question number one when is stage two process validation data required for a new bla submission answer a never answer B in all

instances answer C upon the request of the review team or answer D only for combination products the answer here is B in all instances and with that I will thank you for your time and invite Dr Christopher Downey to continue the presentation thank you thanks John as Joel said I'm Chris Downey I'm the director of the division of biotechnology manufacturing and Cedar's office of pharmaceutical manufacturing

assessment in this next section I'll be discussing the pre-license inspection portion of Cedar's biologics license application assessments pre-licensed inspections or plis are conducted by Cedar as part of our biologics license application review process these inspections are led by Cedar and the senior team includes a team of experts in application assessments who are both experts in assessment and inspection these are distinct from surveillance post-approval or for

cause inspections which are led by the office of Regulatory Affairs plis assess the facility and Manufacturing process for the subject product of the bla and they observe the bla product during its manufacture because of this the applicant provides a manufacturing schedule at the time of submission and works with the cedar Inspection Team to plan the inspection to meet this requirement applicants are expected to have knowledge

and control of all stages of the manufacturing process and I want to highlight that this includes manufacturing and testing activities that are conducted at Contract manufacturing organizations or CMOS the facility assessment is a key part of the application for Cedar assessments and an acceptable outcome of the facility inspection is required for application approval see their pre-licensed inspections have a number of objectives on these inspections assess

the Readiness for commercial manufacturing and the biologic that's the subject of the application and this includes not only an assessment of cgmps but also an examination of product specific procedures and controls equipment facilities cleaning contamination and cross-contamination prevention procedures Personnel training things like that conformance of what is actually performing the facility with the information that's provided in the application as well as the procedures and controls

in place to ensure data Integrity in other words that the data that we see in the bla is reliable and was conduct collected in a in a way that's transparent and well documented are also examined the inspection provides a holistic assessment of whether the firm's quality system and by extension the applicants has sufficient knowledge and control of the manufacturing process and controls to assure the final

quality of the product s about biologic facility inspections are risk-based which means that all facilities and applications are assessed for whether an inspection is needed and what inspectional tools Cedar might use as part of the application review this assessment as I said is risk-based and considers the previous inspection history of each facility which includes whether it has been inspected at all or if it has been

inspected whether the observations or other information in the inspection reports suggests that there is risk that we need to assess the inspection history assessment also considers information shared by trusted Regulatory Agencies which might be shared for example through mutual recognition agreements we also consider whether the facility has experience with a similar manufacturing process to the one that's the subject of the pla we also look at

whether the process uses new or novel Technologies or if the Technologies are new to the facility or applicant and we also assess if there are specific risks identified from the application review itself FDA has a wide variety of inspectional assessment tools available to it the backbone of Cedar's inspection program is information gained by FDA inspections both those conducted by Cedar and of course those conducted by

the office Regulatory Affairs and we use the information we gain from those inspections in risk-based ways but we have additional tools available to us as alternatives to inspections or to some to augment inspections the first such tool is reference requests made under seven section 04 A4 of the food drug and cosmetic Act this document review information can be used in advance of or even in lieu

of an inspection the second tool is what's called a remote interactive evaluation or Rie in which interactive technology can be used to live stream or view pre-recorded videos of things like facilities operations excuse me data or other information that we use in our assessment or to interview staff at the facility I want to highlight that providing documents that are requested through the 704 A4 records request

is mandatory whereas participation in a remote interactive evaluation is voluntary however a facility declining to participate in a remote evaluation does not eliminate our need to conduct our assessment and so FDA will need to use other tools which might include an inspection in those cases if we've selected a remote evaluation as a way to expedite the process having to do an inspection instead maybe a slower

process to complete than a remote evaluation and as we noted in the previous slide we also use information gain from foreign Partners under mutual recognition agreements or other confidentiality agreements to share information and I want to note that the availability of a previous inspection report from a say an MRA partner does not necessarily replace the need for an inspection just because they had an inspection with

a successful outcome doesn't automatically mean that we wouldn't need to inspect but we do use that information as part of our risk assessment and the more information we have the better decision we can think about what kind of tools we can use so further ask question of using remote regulatory tools is alternatives to bla inspections the use of remote tools such as record requests or remote

evaluations to replace a shortened inspections is a risk-based decision and that decision is made by the cedar review team the team considers all available information some of which might not be known in the facility or the applicant and we consider risk factors such as the previous facility inspection history process risks microbiology concerns product concerns things like that we also consider whether the use of remote tools

can adequately support or mitigate the need for an inspection and in so doing potentially save the the facility and the applicant and the agency resources we of course we also consider the impact of travel restrictions for example during the covid-19 pandemic we use remote interact evaluation Tools in cases where we weren't able to travel [Music] because of all these factors fa does not consider requests to

use remote tools from facility or applicants we instead make a decision as a team as to whether and what remote tools may be used and then once a decision is made we will contact the facility to request either things like documents from a 704a4 records request or to request use of a remote interactive evaluation so this brings us to our Second Challenge question can a bla

be approved with outstanding facilitated efficiencies a yes if the facility is commits to correcting them B yes if the facility requests a follow-up remote regulatory evaluation C no satisfactory facility evaluations are required for an approval or Des but only for 355a or non-biosimilar applications [Music] and the answer is C successful facility evaluations are a requirement for approval all right so moving into our next section this

I will discuss an assessment that Joel and I did a recent complete response actions and the natures of the deficiencies that were identified in the complete spot response letters so we surveyed a predetermined subset of complete response actions for Cedar Blas over roughly the last three years and we assessed that efficiencies identified we looked at a total of 32 complete response actions each letter might identify

more than one facility and a single bla may have had more than one complete response letter so you'll see in the subsequent slide that there are more than 32 deficiencies I would also note that the 32 Blas also included 15 biosimilar applications [Music] so this first chart sorts the sea art efficiencies into four broad categories and identifies the number of times each deficiency sorry A deficiency

in each category occurred the four categories were one clinical or related issues two issues related to the facilities where the manufacturing occurs three issues in the chemistry manufacturing and control sections of the bla dossier itself for issues in the data that would support the biosimilarity of a biosimilar to its reference product and we found that the most common deficiencies were facility and inspection related issues non-facility

issues in the CMC dossier along with clinical information was the next most common notably the lack of demonstration of bias similar to the reference product was not the most common deficiency for biosimilars facility or other CMC issues were so unpacking the facility issues a little further we categorize the types of facility issues into 11 sub-categories these subcategories are not necessarily mutually exclusive and I use a

little bit of judgment in sorting them so an efficiency might fall into more than one category so those caveats noticed or noted I mean the most common issues were related to cleaning procedures and controls environmenting procedures and bioverted control as well as contamination and cross-contamination controls the theme that occurred the most often was concerns about quality oversight which is things like did the firm conduct thorough

investigations and deviations and did they take sufficient corrective actions did they adhere to their written procedures that they have good documentation practices do they assure training of their staff it's important to understand that issues that were sufficient enough to Warrant a complete response action are often not resolved until there is a follow-up inspection that can verify the effectiveness and implementation of corrective actions so it really

is a big delay to have to to make Corrections of the facility so to ensure that new products are brought to the market as quickly as possible I think this information tells us how critical it is to development programs that applicants ensure that their facilities and their Quality Systems are ready for commercial manufacture commercial production commercial level GMP standards the for submitting a bla so next

we examine the deficiencies in the CMC sections of a bla dossier other than those related to bio similarity once again these categories are not necessarily mutually exclusive so there's a little bit of judgment call in these sortings as you can see microbial control of both drug substance and Drug product was a frequent concern as were other manufacturing controls and validation specifications and issues related to stability

testing and stability programs were also quite common what are the specification stability controls regarding the reference standard qualification and re-qualification some reference standards come up as well we also saw that control of cell Banks and other such critical inputs was a recurring source of issues so the key conclusions for the CR evaluation this survey of CR deficiencies were that facility issues were the most common reason

for complete responses and CMC dossier issues other than the facilities and clinical efficiency were the next most common for by a similar facility and CMC deficiencies are more common than issues in demonstrating the biosimilarity of the reference product we covered how CMC issues can span a variety of topics this includes manufacturing and process control microbiology uh being the largest categories specifications analytical methods stability including those

for controlling reference standards are frequently CR issues as are issues in cell banking inspection issues span a variety of topics including environmental monitoring equipment cleaning aseptic procedures but I think even more importantly insufficient oversight by the quality system was the most common theme that our inspectors brought to us this underscores that site selection and Readiness for commercial manufacture are Paramount to biologics development so our third

challenge question is for Blas and Cedar which receive a complete response what are some potential causes a CRS may occur only for clinical reasons B CRS may occur for manufacturing facility reasons C clinical product quality and Manufacturing facility region reasons are all common causes or Dean of the above and the answer is C all sorts of issues including manufacturing quality and facilities are common causes this

slide provides some handy hyperlinks to some of the things that are related to some of the things we talked about and can provide additional information and finally in summary I hope we've demonstrated for you that biologic products have unique scientific and Regulatory considerations that inspection plays a critical role in senior's assessment of Blas and that we use a variety of tools as part of our inspectional

assessment and finally the successful development of biologics requires CMC development along with clinical development and this CMC development includes ensuring the Readiness manufacturing facilities for commercial production and with that we'd be happy to discuss any questions with you and thank you so much for coming today thank you all for the great presentations as we move into our final q a panel if you haven't had a

chance to submit your questions in the Q a chat pod please do so now latches many questions last time allows to Doris Chen and from his chin is it the location of the agent or the initial importer which dictates where a foreign manufacturer's shall report to hi great question um the foreign manufacturer of the geographical location of the U.S agent is is determines uh which Ora

conducts a recall if you have repackaged the API if you're a distributor that sells you know these API ingredients and you've repackaged it you should conduct a downstream recall on your own and send notifications to your consonants if you use those um either the API or an excipient in a finished product um your finished product is now adulterated because you made it with recalled products so

you would contact your Ora Farm recall coordinator and conduct your own recall thank you thank you for responding to that question we've got a couple more questions from this chin and here's the next question is the recalls and shortages team the same as the drug shortage team great question no no so shortages team is in the office of compliance and we coordinate with our colleagues in

the office of compliance to evaluate and make regulatory decisions to allow a defective product to remain on the market if the benefit outweighs the risks the drug shortages team is in the office of the center director and they work with other groups such as the office of new drugs office of pharmaceutical quality office of biotechnology products and division of microbiology assessment and they evaluate the safety

and clinical impact of the defective product to make a recommendation of benefit over risk thanks thank you for responding to that question we have one more question from Miss Chen in this round and here's the question I have a defective product that currently is on the drug shortage list but I don't think that this will cause a disruption in market supply who should I contact to

discuss if I can move forward with my recall hi so that is um a great question if you don't believe your Market action is going to cause a disruption in Supply you would contact your Ora Farm recall coordinator before you initiate your recall and um provide information like quantity of product distributed the dates of distribution for your proposed recall Lots FDA is also going to want

to know your planned amounts and dates for replacement of your recalled products so Ora Farm will send this information to my team who will verify that your Market action doesn't exacerbate a current shortage or create a shortage and we want to do this before you initiate your recall um the drug shortage team will evaluate your Market action and its impact across all suppliers of the product

so please wait for Ora Farm to relay that our team has contacted drug shortages before you move forward with your recall if you believe your product will cause or exacerbate a shortage you would reach out with your proposal to the drug shortage team and that information um is located on my slides thank you thank you for responding to that group of questions moving on to our

next panelists we've got a group of questions that came in for Dr Joel Welch and here's the first question for Dr Welch what if you have a trimer of proteins and varying length from 35 to 55 amino acids what division would you work with C der or C Burr so thank you for that question it's a very good one I think you can appreciate from our

presentation we tried to create and provide some general Frameworks for how these pro products are regulated and classified certainly when there are unique complexities around a particular product and where it should be and how it should be regulated the easiest and recommended path would be to request a designation a request for designation submission is described on the FDA website and that would be the most appropriate

mechanism to figure out where where your product would reside and how it would be regulated so we would recommend you reach out that way to to get a firm response for a specific case thank you for the question thank you for responding to that question we have a few more questions for Dr Welch and here's the next question how many PPQ batches are considered appropriate for

biologics two or three so thank you for that question um there in in the cgmps and FDA policy there is not a specified minimum number of batches to validate a manufacturing process rather FDA recognizes and acknowledges that that any manufacturing process or process or even a change to process can't be necessarily boiled down to a specific number of batches rather amendment of number of conformance batches

is typically needed to validate a process but we expect sponsors to have a sound rationale for its choice for for what that looks like and to and to approach the agency with with science-based approaches for for how they would intend to complete process validation if there are specific questions about a validation program that's always a good topic for a potential meeting with the agency under the

appropriate user fee program thank you for the question thank you for responding to that question we have one more question for Dr Welch in this round and here's the question our type 2 dmfs of biological manufacturing platform DS intermediate the DS and DS permissible for biologics IND great question thank you for that um in general it is it is potentially permissible to use a type 2

DMF in those cases under an IND the best resource to understand a little bit more of those limits would be the 2019 FDA proposed rule on type 2 DMS for biological products it's on the Federal Register website and it would provide more specificity including limits around emfs but in general it is permissible to potentially use them under an IND thank you for the question thank you

for responding to that group of questions moving on to our next panelists we've got a group of questions that came in for Dr Christopher Downey and here's the first question for Dr Downey would FDA agree with an applicant timing it's ble submission such that a validation protocol is submitted in the bla and an executed validation files and the validation report are complete and reviewable during a

pre-license inspection foreign thank you for the interesting question um in general the answer the short answer would be no um the application is expected to be complete at the time of submission and that would include the the process validation is complete and the report is available in the submission that is reviewed as part of the bla review it's not reviewed as part of the inspection um

so the inspection is is is more facility specific than that so the the inspectors aren't reviewing application materials as part of their inspection generator they're in view they're reviewing them um the facility practices and gmps and how that facility is performing the the stuff described in the application um in rare cases with the Breakthrough product or an expanded program we we might discuss with an applicant

if they have fewer than three PPQ batches the potential of submitting a concurrent validation protocol where they would submit um partial validation values native from an initial batch and then um additional validation post approval but that's sort of not the norm it would be um something that would need to be worked out in advance with that game thank you thank you for responding to that question

we have a few more questions for Dr Downey and here's the next question could you elaborate on one of the inspection deficiencies conformance to application yes thank you for following up on that one as well I think I alluded to it in my previous answer um the confirmness application means is what the manufacturing and testing activities being performed at the facility do those match what is

described in the application um I know from my own experience for example I've been on an inspection where there were there were manufacturing steps being performed um at the facility that weren't described in the application um and so that's that can make a potential concern and one of our objectives of an inspection is making sure that the process we are licensing is uh matches the process

is actually performed on site at the facility thank you thank you for responding to that question we've got a couple more questions for Dr Downey here's the next question how soon would a follow-up inspection be conducted thanks um there's there's not a set time that a pre-licensed inspection is is tied to the the timing of that is tied to the submission of a bla application and

the manufacturing schedule of the of the facility itself so if an inspection generated observations that ultimately led to the facility not being approvable um whether there is an additional inspection needed would be that decision would be made during the review of the resubmitted bla and um again might be dependent on the manufacturing schedule of the operations performed for that application that's submitted by the applicant so

it it really depends on on the applicant um that said it's I think it's important to highlight that the the corrective actions should be in place and the facility should be ready to be reinspected it doesn't do any good to immediately resubmit an application that has received a complete response if the facility isn't completed with its corrective actions or have data to support that the corrective

actions are effective because um you know if FDA goes back and the issues are still there then they'll be the same observations again and and ultimately the application could again not be approvable and now the essentially the time has been wasted by them by the applicant submitting too soon so it's it's it's somewhat dependent on resolving the timeline of resolving the problems and the strategy of

the applicant in terms of how they uh they determine that and resubmit their application thank you thank you for responding to that question we've got just barely over a minute left I'm going to try to squeeze in one more question for Dr Dowdy and here's the question can you comment on the FDA view a Reliance on a mutual recognition agreements and applicability to inspections yes so

we we utilize Mutual recognition agreement partner inspections and we evaluate their reports and that goes into our risk assessment in terms of what type of inspectional assessment is needed um you have to bear in mind that the the partner may not have covered the same products on their previous inspections it may have only been a GMP inspection it may not have the same um products or

objectives as a FDA pre-licensed inspection so it may not by itself eliminate the need for an inspection but we we do rely on the information available to determine um risk for the facility and if if there's a lot known about uh the the product already from that inspection that can that can help us determine the facilities no risk and make decisions in that way thank you

well that's all the time we have for questions in this panel and we want to give a huge thank you to all of our presenters and panelists for fantastic presentations and answering numerous questions that came in during all the Q a panels we have the pleasure of welcoming back for closing remarks our small business and industry assistance director Captain Brenda Stoddard welcome Captain's daughter thank you

very much Captain Ford well everyone sadly we have come to the conclusion of a seated drugs track ready 2023 and I truly hope that you have enjoyed the two days and have found many if not most of the presentations to be helpful to you worthy of saving as references and sharing with your colleagues we have covered a lot of territory in the past 48 hours and

I am truly impressed and reassured with its relevance and that so many of you attended from literally all over the globe and so many of you stayed with us until now the very end I thank every one of you also our presenters and panelists for their exceptional presentations and very expensive q a sessions and of course our technical staff handling and troubleshooting all the logistics behind

the scenes my thanks also to sbias Captain Ray Ford and Lieutenant Commander renulau for moderating over the two days within the overall context of producer 7 pursue for three and a mover we provided the most current intelligence and many Cedar programs we address the various user fee meetings bioinformatics and electronic submission practicalities we discussed digital Health Technologies from the review and I.T perspectives we took a

look at a couple of our pilot programs at user-related risk analysis and human factor protocol reviews we provided valuable information on decentralized clinical trials and post-marketing commitment we gave you very timely insight and already sees and point advancement pilot program and then we wrapped up with cmcs and its development and Readiness pilot program recalls and biologic manufacturing inspections it is my firm belief that if you

walk away today with validation of your current processes or perhaps you realize that you were not doing things as your FDA recommends and now you know exactly what to do if you receive new and applicable information you've got responses and clarification on your questions then sbia would have achievous purpose and to emphasize the one recurring theme in all our presentations and Q a sessions and that

is to contact ceter early and often this approach is in everyone's best interest