A question on prototype devices:

 QUES:  

My company is a small startup  We want to get proceed into certifications and regulatory approval using a “production equivalent prototype”. This prototype is identical in design to our planned production model (equivalent design controls), however the materials and manufacturing methods of a few of the external enclosure parts will be different. We need to do this because we don’t have the funding to create production molds for these parts and we would rather use cheaper methods/materials to get through regulatory before we invest huge sums of money into production.

 

My question for you is: If we take this approach and use the pre-production materials for completing regulatory approval do you think we will need submit another 510k when we want to move into higher volume production in the future? We plan on providing test data showing the enclosure still passes 60601-1 (we will get another report done through our test lab), provide data showing performance of clinical function is within tolerance to the production prototype and justify that the production method/materials are better controlled and higher preforming than the production equivalent prototype?

 

 ANS:  By certification, I assume the product is to be sold outside the US and you have to hire a Notified-Body to certify your QMS, some inspections in manufacturing and your Technical File.  The  US FDA has a registration process.  All have fees associated with them.

 

The FDA specifically requires that the product tested for regulatory submission be equivalent to what will be sold, e.g., Design Control 21 CFR 820.30, under (g) Design validation - "shall include testing of production units under actual or simulated use conditions." 

 

Changes in material (and resulting electrical characteristics, biocompatibility issues, etc.), IF they impact safety and effectiveness, require a new 510(k); if validation data shows no new impacts on S and E (see the two Guidance Documents on changes to devices having a 510(k) requiring submitting a new 510(k)) then the test data would be sufficient (retained in your device's DHF, subject to FDA inspection) and no new 510(k) would be required.

 

Your proposed method carries a high degree of risk on the surface, and its success would be dependent upon solid test / verification and validation data showing at least equivalence if not some superiority. However, since this is an enclosure there would be less safety issues, I'd assume. However, companies do occasionally use short life tooling initially for molded parts, changing to more expensive and durable tooling as market acceptance increases, and usually validation is sufficient to address the S&E issues. 

 

QUES:  I think we can justify that the initial device tested for regulatory submission can be considered a “production unit” but it would only be feasible for small scale initial production runs. If our product were to build up demand, we would need to switch to an injected part. We hoped we could do this with an engineering design change with additional, testing, data and documentation as I described below. We would want to avoid having to submit another 510k if we did need to make this modification, but I really can’t see how we would reduce S&E with this change.  The high production unit parts would be stronger, have a more controlled production method and have more examples of successful biocompatibility assessments, therefore I think there is little risk that the test data shows a reduction.

 

My main concern is that FDA would see the production method change and have an issue with that aspect of this design change. Let me know what you think.

 

ANS: If the only change is from limited tooling to high-volume tooling, it's not an issue.  If the change is from thermo forming or similiar to high volume injection molding that should not be an issue that can't be addressed by robust V&V.  If that change is coupled with a material change then this is the area of major concern, but can usually be addressed with all necessary test data showing same or better resolution of S&E with the injection molded part.  Those two Guidance Documents on changes and the 510(k) do allow for good QSR / V&V data to address the S&E, possibly eliminating the need for a new 510(k) (S&E is what an FDA review of a 510(k) focuses on).  

-- jel@jelincoln.com

A question received in my webinar on the EU's Clinical Trials Regulation presentation

 QUES:  Is there a specific section or chapter or any detailed considerations described for cell and gene therapies and how to deal with them in contrast to conventional drugs under the new Regulation ?

 

ANS:  Short answer:  No.  Long answer:  The CTR is a high level document, focused on subject safety and accuracy of the data generated.  Also the simplification of the submission process.  It discusses a risk-based (patient risk) approach to the submission documentation:  By defining low intervention trials, EU-CTR enables a risk-based approach that EU-CTD could not sustain. Consequently, sponsors of low intervention studies may enjoy simpler submission dossiers (e.g., Summary of Product Characteristics [SmPC] used rather than IMP Dossier [IMPD]). They also may experience less stringent rules for monitoring, the content of the Trial Master File (TMF) and investigational product (IP) release. 

 

The sponsor's claim of low-intervention or not is evaluated upon submission to the EU portal by qualified individuals in the assessing Member State - see CTR Articles 5.2, 6 and 25.

 

The cell and gene therapies trials would likely fall into a higher risk intervention trial, requiring more detailed submission dossiers, and tighter assessment and monitoring, etc., rules and release to the market evaluations.

-- jel@jelincoln.com

A MAJOR CHANGE IS COMING!

 The FDA has been working to align its QSR (21 CFR 820, the device CGMPs) with the worldwide quality systems device standard ISO 13485. FDA published the proposed amendment to 21 CFR Part 820: "Medical Devices; Quality System Regulation Amendments", on February 23, 2022; harmonizing the current Quality System regulation for medical devices by converging its requirements with international quality management system requirements. 

Part of the reason for harmonizing its regulations with ISO 13485 is to reduce the regulatory burden for device makers who sell product in both the US and in EU / Asia, by eliminating redundancies involved in complying with both the ISO and QSR (Quality System Regulation) standards. After years of reviews, the Agency has determined that the requirements in ISO 13485 are, when considered as a whole, "substantially similar to the requirements of the current Part 820, providing a similar level of assurance in a firm’s quality management system and ability to consistently manufacture devices that are safe and effective and otherwise in compliance with the FD&C Act.” They base this decision on their past participation in the Medical Device Single Audit Program (MDSAP), as well as a previous audit report pilot program in which the Agency accepted manufacturers' N-B audit reports based on ISO 13485 (-:2003) in lieu of an FDA QSR compliance inspections. FDA agrees that ISO 13485 represents a more modern QMS approach and “has greater integration of risk management activities and stronger ties to ISO 14971, the risk management standard for medical devices". 

What will the new Quality Management System Regulation (QMSR) require?  A key element is the incorporation of ISO 13485 into the new 820 by reference.  Major emphasis will be upon risk management in accordance with ISO 14971 (-:2019), which currently has only a brief reference  in 820.30.  The FDA views risk management as an “essential systematic practice” to ensure that devices are safe and effective. If the proposed QMSR rule is finalized, it will enhance some parts of ISO 13485 under the revised 820 portion of the rule.  

Device  manufacturers will need to enhance risk management procedures for specific devices and in all other areas of their businesses to align with the QMSR.  Design Control (ISO 13485 7.3 Design and Development) will have limited application to Class I devices, but fully involve Class II and III (US classifications) as is currently done in the US but not the EU.   Traceability of implantable devices will be emphasized more than in  ISO 13485. The QMSR will re-emphasize senior management's importance establishing and maintaining a policy of quality, and a company culture of quality. The concept and definition of the make-up and role of "the customer", a term familiar to ISO but not the old QSR.

There are other changes as well. Combination products' CGMPs, 21 CFR 4, will be modified to include reference to ISO 13485.  QSIT will be changed.  The FDA's new inspection program would not be a substitute for an ISO 13485 certification procedure if one is required, nor would those who hold an ISO 13485 certificate be exempt from FDA inspection. Once the final rule is approved, the FDA proposes to give manufacturers one year from the publication of the final rule to adapt to the new regulatory requirements.

Our clients are already ahead of the curve on this change.  SOPs and QMs that we have written for the past 15+ years have included references to ISO 13485, as well as the current version of 820.  As a result, they will require less revision than otherwise.

-- jel@jelincoln.com

Question on Yield and OEE in Phama Production Lots

• QUES:  I read in some FDA document about yield. I have seen some warning letters exactly on this topic as well. However, there are many instances where OEE is prepared instead of yield. And classified as Non GMP. Are these 2 different things ? And should OEE be classified as Non-GMP ?

• View John E.’s profile
  

  
  

  ANS:  OEE = Overall Equipment Effectiveness (OEE).  OEE is a measure of how effectively a manufacturing operation is being utilized.  I can't give you an FDA "approved" answer as I have no information / experience from them on that subject.  My personal opinion currently is that I would not recommend substituting one for the other.  Yield is a specific lab calculation(s) required under the CGMPs for various processes in / during and at the end of a lot and logged as part of the batch record. OEE is more a manufacturing process utilization measurement, usually more generalized, which could be part of the CGMPs P&PC "tools" but is not specifically mandated in the CGMPs.  And you have to meet the CGMPs. If you could show a 100% correlation between the two at the level of the requirements of yield and its intervals required in the process for each lot, and the OEE data is handled under the rigors / documentation of the CGMPs, you may have a rationale for such use, but that's highly ify and I can't comment on that vis-a-vis your operation.  

• -- jel@jelincoln.com

 Questions on FDA Registration and 510(k) by an Asian client on a facility move:

QUES 1) The unit which we are delisting, will this be subjected to any USFDA
audit for the production done so far ?

 

ANS:  All production is subject to review / audit by the Agency, usually if there are problems. Once the facility is shut down, such review is only done on the existing records, lot / batch records, logs, validation test reports, etc.  I recommend you do a shut down verification per one of my previous e-mails I just sent you, to verify that everything was operating in specification for the last lot / last item in the last lot produced.

   
QUES 2) The US FDA 510K was first given to the XXXX unit and now is also
available to the YYYY unit. The 510K is very important for us and I am assuming that even if we remove the old unit it will not affect the 510K given to our company.

 

ANS:  The 510(k) remains with the company, unless it's sold with the device. The company's address can change, but that doesn't change the 510(k)'s  ownership.  The FDA however currently has no way to update old 510(k)s on file with them, 'tho they recognize that's a problem.

 

However whenever you change production locations, equipment, processes tied to a 510(k), you are responsible to revalidate the things that changed or moved to prove that the product is still being made the same (and as documented in the 510(k) - see the two guidance documents on changes to devices and the 510(k)') and no quality issues have arisen as a result of the move / changes.

-- jel@jelincoln.com 

 Some European Companies Selling in the US Aren't Playing By the Rules

As a consultant working with clients all over the world, I sometimes get push-back to a recommended action using reasoning similar to the following:

Most of the pharma facilities in this area are not following the cGMP rules, even though they sell to USA market.  This happens when if they bring in new equipment. The facilities here are almost 20-30 years old and they all seem to have the understanding that if they print the batch record on a paper then they are free from Part 11 requirements. They don't do cleaning after each run.  They claim they only use a paper system, and aren't under 21  CFR Part 11. Some companies are doing API manufacturing in a non-sterile environment, not good aseptic processing . Some are installing new equipment, but with no proper (or only haphazard)  verification / validation, and many other non-conformances. It doesn't appear that the FDA has been here for inspections. So, if my competitors are not obligated to follow the cGMPs, why should I?

I usually answer similarly to the following:

If the companies sell in the US they are required to follow the US FDA CGMPs for their
industry, e.g., 21 CFR 820 for devices, and 21 CFR 210, -211plus for drugs.  They don't need 

to follow 21 CFR11 if they used paper records and manual signatures, BUT all their people 

have to do that.  If some are using the e-records / e-signatures to do CGMP activities / 

records, then it doesn't matter what they say their policy is, they're viewed as under Part 11 

by the US FDA.  

The FDA has 11 resident posts located world-wide, outside the US, 3 in mainland China.  They

are still backlogged due to COVID19 in inspections, and they base the frequency of

those inspections on the company's products' risk to patient.  But I have worked with some 

EU companies that have had US FDA inspections and gotten Warning Letters, ditto Asia, so 

the FDA is currently inspecting some companies in the EU and Asia.  Those companies had 

previously had greatnotified body audits, incidentally.  The CGMP disconnects I see are usually with the biggest 

problems in CAPA, Trending, andthe definition of risk (the FDA focuses on patient safety, many EU and Asian companies also include      

financial, regulatory, schedules under risk as well).  I see a lot of problems with V&V all over the 

world, including in the US.Some validations not holding variables constant, e.g., with written P/Ns and specs, change control,

key variables not validated, no predetermined acceptance criteria set before running the V&V, et al.

Sad to say, I see the same things that you've mentioned.  As a consultant, I usually get called after 

an FDA Inspection, when the company gets a lot of 483 observations and/or a Warning Letter for

for things they should have been doing all along but weren't.

Some current Covid 19 vaccine start-up production issues, drug 

shortages, and baby formula shortage problems here in the US were due to failures in cross-

contamination controls, basic CGMPs. In some cases, they've been misinformed by another consultant.

I try to educate such companies and their personnel, but some feel I'm only requiring some document

to "pad my fee", so, sad to say they'll find out the hard way when they finally are inspected and get a 

Warning Letter, or are shut down after some of their customers in the field get sick or die.

-- jel@jelincoln.com

 Equipment Software / Firmware V&V, Part 11 Issues

QUES:  I read some of your articles on IVT network. Content of the articles are very clear and informative. I still have some questions though. Can I ask if you don't mind ? For medical device manufacturing industry, we follow 21 cfr 820, 21 cfr 11. Under 21 cfr 820 there is Device Master Record, Device History Record & Device History File.

 Let's say there are 3 machines used for manufacturing a FDA regulated medical device. 1. Inspection Machine, 2. Assembly Machine, 3. Blister Machine. Q:Will these machines at any stage create electronic Record that we must preserve under FDA regulations? E.g., Recipes/ configurations, Visual Inspection (Quality Related) pictures of Labels, Alarms

ANS:  The CGMPs for devices, 21 CFR 820 require a DMR or recipe for how the device is built (BOM template, references to applicable assembly and test SOPs, drawings, required labeling, traveler template, etc.). The DHR or lot record provides proof that the DMR was followed for that lot, e.g., the BOM is filled out with lot numbers and quantities of each part used, the traveler documents line clearances, machine settings, QC test results, etc.. These records may be kept manually / paper, or electronically. If kept electronically, or if E-SOPs, etc., are used, then 21 CFR 11 becomes operable, and any computer systems used to generate, use, save, change those e-records / e-signatures must be validated, to include Part 11 issues, e.g., audit trails, date / time stamping, et al. That would include the three pieces of equipment you mention; if they generate an e-record to be used in proving CGMP compliance (to 820) to be retained in the DHR, etc., then they have to include Part 11 issues as part of the required validation. Since all equipment must be validated, and all software / firmware must be validated. If the equipment uses software to run, but not to generate records (i.e., you record the information to set or run the equipment and capture any data manually (e.g., manually write info on the traveler), then the equipment and its software would be validated as normally (e.g., IQ, OQ, PQs), but Part 11 elements would not be part of the validation. Part 11 only becomes a requirement if you are using e-records and/or e-signatures in lieu of paper records and/or manual signatures, to prove or satisfy a CGMP requirement / provide a CGMP record.

QUES:  Thanks a lot John for the Answer 🙂 To give you a clearer picture, We have SAP which creates the batch number, expiry date, units to be produced etc and sends to SCADA. Machines receive this information from SCADA. So there is no communication from Machine Control system to SAP. What else SCADA communicates to Machines & vice versa? Recipe Name, good/bad items produced, Machine states(Running/stopped/aborted, etc.) but no Alarms are communicated. Also, there is a significant amount of Machine Parameters configurations (also a part of Machine recipe) needed to produce the Items, remain in machine. It's not recorded anywhere else, only in machine. But machines don't have Electronic signature at any stage. SCADA also maintains the EBR. Like line clearance, goods received etc Electronic signature is maintained in SCADA to validate the changes. We also have Electronic Document Management System where we have DMR, DHF. Change control is maintained in this EDMS.  

ANS:  Basically what you described fits what I sent you previously.  Not only does the computer systems need to be validated per 21 CFR 820, but those computer / electronic systems involved in facilitating and/or  documenting CGMP actions (if any) also need to be validated to 21 CFR 11 on top of the general CGMP validation (I usually add Pt 11 test cases to the OQ).

-- Jel@jelincoln.com

Also, where validated machines generate data that needs to be retained in the GMP record, instead of the normal data integrity requirement of two signature, one entry, one verification, only one signature is required, one verification. -- JEL 09/19/2023

 Human Factors / Usability Engineering Question:

QUES:  As you mentioned on the webinar, the usability engineering is done as needed based on the product. So how should we decide if we need the usability engineering on specific product? Take anesthesia needles as an example, we know this is a mature design on the market for a long time. Is there any way to prove that this similar design won’t cause any use error? By MAUDE or adverse events?"

 

ANS:  The question is -  "How similar is the new design to the old one, as to whether it raises new issues of safety and efficacy, especially around ease / safety of use?" Not -  that a current design precludes an occasional use error, as there will always be an infrequent use error with any device, even one with an optimized design for safety / intuitive use. If the new product's design is substantially unchanged, and has a long field use history, so that it's use / use interface issues would be the same as the predicate's design, then there's no need for a usability engineering study.  Your SOP on HF / UE should discuss and allow these approaches, then you have to follow your SOP. Document your rationale.

FDA's 2016 Guidance on HF / UE:  

"As part of their design controls, manufacturers conduct a risk analysis that includes the risks associated with device use and the measures implemented to reduce those risks. ANSI/AAMI/ISO 14971, Medical Devices – Application of risk management to medical devices, defines risk as the combination of the probability of occurrence of harm and the severity of the potential harm. However, because probability is very difficult to determine for use errors, and in fact many use errors cannot be anticipated until device use is simulated and observed, the severity of the potential harm is more meaningful for determining the need to eliminate (design out) or reduce resulting harm. If the results of risk analysis indicate that use errors could cause serious harm to the patient or the device user, then the manufacturer should apply appropriate human factors or usability engineering processes according to this guidance document. This is also the case if a manufacturer is modifying a marketed device to correct design deficiencies associated with use, particularly as a corrective and preventive action (CAPA)."  

--  https://www.fda.gov/media/80481/download , pg 2, para 1

 

Yes, MAUDE / adverse events would be one of several (see the UE File template example in my slides) possible sources to check.  If there could be a questions as the need to do a UE analysis, and you chose not to, you could do a one or two page plus "UE File" stating the limited analysis done to reach the conclusion that a full-blown study was not needed.

Patient / Device Risk Management (ISO 14971) is always done on new device and major change to existing devices.  Human factors / usability engineering is done as needed, per the above in red.  Each activity is described in a File, which is part of Design Control (or CGMP Change Control) depending on where or when in the product's life cycle the initial design or design change is initiated. 

 

-- jel@jelincoln.com 

To the first paragraph under "answer", added new last sentence on "document your answer." - JEL 05/01/24

 

Mil Std 105E  Sampling Plans Not Dead Yet

Mil Std 105 E was officially cancelled in 1995 and replaced by ANSI/ASQ Z 1.4 for sampling by attributes.  At that time I purchased a copy of Z 1.4 (for a fee ~$199.00, and copyrighted; whereas the Mil Std stated that its "distribution was unlimited" - no fees and no copyright worries), and started to switch my clients over to Z 1.4. But in checking I found that the Z 1.4  sampling plan was identical to the 105E's, so I went back to 105E with those of my clients who hadn't updated / wanted that type of plan, using the105E's plans copied in the SOP's I wrote for them, without having to purchase Z 1.4 / updates for every client and worrying about the associated copyright issues. 

However, one of my clients had an FDA CGMP compliance inspection, and was called out for using 105E, an "obsoleted standard" for acceptance sampling, and the FDA inspector was adamant in the need to change to an alternative. I couldn't convince the inspector that the plans were identical, so, rather than argue, we changed (in a couple of instances, to Nicholas Segura's C=0, also for a fee and copyrighted, and derived from Z 1.4).  

Recently, while updating an QC inspection SOP, I stumbled upon some older Quality Digest articles arguing for the advantages of the old Mil Std105E, and which referenced ASTM E2234, which "carries forward" that standard (e.g., see Wikipedia reference below).  So now I once again have Mil Std 105 E as an option for clients for its sampling plans for QC sampling in CGMP applications in medical device manufacturing, because they have always been and are still valid, but I now had a valid, easy to understand rationale for their continued use.       

"MIL-STD-105 was a United States defense standard that provided procedures and tables for sampling by attributes based on Walter A. Shewhart, Harry Romig, and Harold F. Dodge sampling inspection theories and mathematical formulas. Widely adopted outside of military procurement applications.

The last revision was MIL-STD-105E; it has been carried over in ASTM E2234 - "This practice establishes lot or batch sampling plans and procedures for inspection by attributes using MIL-STD-105E as a basis for sampling a steady stream of lots indexed by acceptance quality limit (AQL). It provides the sampling plans of MIL-STD-105E in ASTM format for use by ASTM committees and others and recognizes the continuing usage of MIL-STD-105E in industries supported by ASTM. This practice also establishes lot or batch sampling plans and procedures for inspection by attributes."

It was officially cancelled in February 1995 by a Notice of Cancellation. This Notice was updated in March 2001 and again in February 2008. The current Notice of Cancellation (Notice 3) recommends that future acquisitions refer to: MIL-STD-1916, "DoD Preferred Methods for Acceptance of Product", or ANSI/ASQ Z1.4, "Sampling Procedures and Tables for Inspection by Attributes"."

-- Wikipedia and ASTM E2234 description (Color added by JEL)

The above information is presented FYI only.

-- jel@jelincoln.com

12/25/2023 - Added additional to ASTM E2234. - JEL

 Recent questions on a webinar on Verification and Validation:

My responses:

 

Ques 1: 

In the handouts the term “pre-approval” is mentioned several times. Going through the recording did not fully make this term clear to me. Would be great to have some details on what´s behind this.

Ans 1:  I use the term when I add to a validation test report a pre-approval signature block.  The document is routed to the stakeholders for review and approval before the validation is run, to get changes and "buy-in" to the format and test cases beforehand.  It reduces the problems of getting post-approvals when the signatories didn't have a chance to agree to and sign off on the proposed validation prior to performing it. Your validation SOP would be written to address this feature if you chose to employ it. 

 

Ques 2: 

I would like your assistance with a question raised during a discussion regarding manufacturing process verification/validation:

In one of the implant’s identified critical processes, a visual inspection (under microscope by a technician) is one of the tools used to validate the process.

 The question we are facing is whether the visual inspection should be in a quantitative scale rather than qualitative.

Please bear in mind that the visual inspection is done by a technician who uses specific criteria for approval/disapproval of the implant.

 

Ans 2:  Quantitative is generally better that qualitative, as subjectivity / interpretation elements are greatly reduced.  But qualitative inspections are used frequently.  How you structure the visual inspection to reduce subjectivity / interpretation would be a key consideration.  One can also be used to complement the other for some inspection elements. And monitoring the results over time will provide the best indication of the effectiveness of a chosen approach, a CGMP requirement anyway.

- jel@jelincoln.com

Definition added 08/30/23:  Qualitative observation results cannot be measured while quantitative observation gives measurable data. Quantities like area, height, weight, temperature, weight, time, speed, etc., are examples of quantitative observation while smell, taste, texture, color, etc., are examples of qualitative observation.

Years ago, on specs on/in injection-molded plastic parts, we changed a qualitative "test" (a subjective "too many") to quantitative (mostly; an unacceptable volume to total black specs per set area per the chart) by implementing the use of a TAPPI Dirt Estimation Chart, with a pass/fail range.  See:

https://www.tappi.org/publications-standards/standards-methods/charts--datase/

- JEL 09/19/2023 

Additional justification for "pre-approval": 

 

FDA's Guidance:  "Analytical Procedures and Methods Validation for Drugs and Biologics", issued July 2015, beginning at line 264: 

     "Validation data must be generated under a protocol approved by the sponsor following current   

     good manufacturing practices with the description of methodology of each validation characteristic       and predetermined and justified acceptance criteria, using qualified instrumentation."

-- color added, similar statements can be found in other such documents.  E.g., Google "What is pre-execution approval of validation test scripts?"  -  JEL 10/13/2023

 Recent Webinar Q&A on the DMR:

QUES: About Device Master Records : Does a listing of documents which are registered on other files can respond to the DMR? For instance if we have the document that needs to be on the DMR on the technical file is it acceptable to not put it on the DMR ? Or do we need to have all the documents in the DMR? In case of subcontracting for the manufacturing of the device : some documents as for instance equipment tests are specific to CMO and we, as order giver don’t have these documents in our system. Is it also acceptable to only mentioned it on our DMR?

ANS:  The DMR is the device “recipe” for your company.  It could include a BOM, assembly SOPs, test SOP, a “Traveler”  having check offs for Line Clearance, Label Reconciliations, operating settings / ranges with operator and QC initials, specs, et al (see 21 CFR 820.181).  

The CMO should have their own DMR for the component(s) they are manufacturing for you, and you would show that completed component P/N that you receive from them on your DMR (that would translate through to your technical file). 

If you are the spec developer not just for the completed device, but also for the components built by the CMO, then you may have to include that P/N’s assembly in your DMR / Technical File.  That may be determined by how the part was developed, who developed it, the contractual arrangements with your CMO, any CMO Quality Agreements with your company, etc. 

When dealing with a CMO the final / parent company has to ensure that all regulatory requirements have been addressed totally, which by the CMO (verified by the company), and the remainder by the company.  The company is ultimately responsible for complete compliance.

I answered the above based on the US FDA / CGMPs; but similar points could be made for the EU MDR and ISO 13485.  

-- jel@jelincoln.com

Typo corrected 08/11/23 - JEL

 Recent Webinar Q&A on Design Verification and Design Validation:

QUES: About design verification and design validation : You have mentioned activities both on design verification and design validation : for instance shelf life, biocompatibility… We have difficulties to understand clearly what activities are design verification and what activities are design validation. Could you please explain us? Does a type of activity can be on both and so what are the differences? 

ANS:  Your company needs to specifically define these terms in an SOP so they can be followed by those using the SOP and simultaneously comply with the CGMPs upon which the SOP is based.  E.g., if I have a medical device that touches the patient, I might have requirements for functionality, biocompatibility, sterility, safety in shipping, etc.

I test each requirement, e.g.,  biocompatibility at a lab per ISO 10993, sterility per applicable ISO standard by a contract lab, do shake / drop / cross country shipping testing, environmental test, packaging seal testing (pull, dye…), functional testing (in-house bench testing, lab testing), etc.  Per my “working definitions” of V&V, I would define each of those tests of a specific requirement as a verification. Put their final versions (of verifications) altogether into a Test Report, and that would by my device Validation Test Report, proving all “user needs”, i.e., requirements (customer requirements, standards, guidance documents, manufacturing capabilities, etc.), have been met.

-- jel@jelincoln.com

Minor additional explanations on V&V added, 12/31/23 - JEL

 

Recent Webinar Q&A on User Needs and Design Inputs:

QUES:  User needs / design inputs : could you clarify (maybe with an example) the definition for user needs and design inputs please ?

ANS:  Your SOP should make that definition, as there can be several variations, all acceptable per the CGMPs.  

When I validate, I list all the “ Requirements / expectations by the various stakeholders (including the FDA and other regulatory agencies)” for the item / process / equipment being validated, which include Marketing specs, Standards, Guidance Docs, Company capabilities, etc.  All of these I define as “user needs”, i.e., the user (patient, clinician …) has wants, but expects the device to adhere to safety standards, operating standards, and other considerations necessary in order to produce a safe and effective device. 

These requirements are changed into specific design elements to meet those requirements, and thereby  would drive/define Design Inputs (820.3(f) “…the physical and performance requirements of a device that are used as a basis for device design”.  These would form the initial Design Inputs.  During development, the initial DIs become initial Design Outputs, which in turn become new initial DI and so on until the final DOs are achieved, approved and the Design (documents, et al) is Approved / Transferred / placed into the system for manufacturing.  The FDA discusses this in one of their documents on Design Control (a slide presentation on inspection of 820.30) where they say that only approved DOs need to be retained: however, I usually encourage my clients to include the key transition interim DIs / DOs as well to maintain a usable development history for the company, not only for the FDA. I usually file the interim DIs / DOs under the DO tab in the DHF - define specifics in your company's SOPs.  

-- jel@jelincoln.com

Added additional info on interim DIs / DOs, 12/31/23 - JEL

 Recent Webinar Q&A on Formative vs Summative Evaluations:

QUES:  About Usability studies : could you explain why formative report is a verification data whereas summative report is a validation data ? Indeed, we considered both documents as verification data for the validation of the instruction for use.

ANS:  I stressed that I use my "working definitions" and that you should develop the same (defined in your SOPs and FOLLOWED); that regulatory agencies give much leeway on definitions as long as they are reasonably covered by ISO / GMP, etc., definitions.

RE:  Formative and summative (per IEC 62366), see FDA Guidance "Applying Human Factors and Usability Engineering to Medical Devices", Guidance, dated February 3, 2016,

page 3, Definition "3.3 Formative evaluation Process of assessing, at one or more stages during the device development process, a user interface or user interactions with the user interface to identify the interface’s strengths and weaknesses and to identify potential use errors that would or could result in harm to the patient or user. " I defined as testing, checking  ... verification;

page 20, footnote 4:  "4 Human factors validation testing is sometimes referred to as “summative usability testing.” However, summative usability testing can be defined differently and some definitions omit essential components of human factors validation testing as described in this guidance document."

Further response to the first question:

 

QUES: Could you explain why formative report is a verification data whereas summative report is a validation data ? Indeed, we considered both documents as verification data for the validation of the instruction for use. 

 

ANS:  You are correct when you state that both your formative evaluations and summative evaluation would be verifications as part of the validation of the IFU.  This is because both are used for another step, that is, the validation of another entity, not the UE / HF device interface. Clarify in the SOP. 

 

However, my above comments are based on UE / HF applications , where formative evaluations/testing are in-process verifications of UE/HF, and summative evaluation is the final validation of the device design interface.  Where those documents satisfy the definitions of formative and summative in evaluation of a device's user interface, if they are used for another application / entity, e.g., IFUs, then both could be considered verifications / tests which become part of the IFU validation.

-- jel@jelincoln.com     

 PLC Ladder Logic Software V&V

A recent question I received after one of my webinars:

Ques:  Software Val as part of the DHF- Do lab equipment processes controlled by Programmable Logic Controllers (PLCs) such as for valves to open a door or for temperature control count as software? Or would they be verified / validated as part of the function they control?

Ans:  You could do it either way, and usually software V&V as I outlined in the webinar addresses both, as I do "black box" software V&V (check software operation by the hardware's operation) for all software validations, to see the software's operation by validating the hardware's operation.

With PLC ladder logic, I do both, "white" and "black box" V&V , i.e., a "code" review by a "white box" review of the ladder logic, often by annotating each "rung" as to what that "rung" says versus what tt actually does, and also by running the process / hardware controlled by the ladder logic ("black box").

As mentioned, this isn't the only way to do it. But it's the approach I have taken and has passed numerous US FDA and EU N-B inspections.  

--   jel@jelincoln.com

The 510(k), IDE, Q-Sub, De Novo and PMA Programs for New (or Substantially Changed) Devices Marketed in the US

The US FDA has several programs by which a new medical device can be marketed in the US. They are basically separated by the US FDA’s Classification under 21 CFR 800-series, which in turn is guided primarily by risk of use to the patient / end user.  Class I devices only have to meet basic regulatory requirements, e.g., General Controls, the CGMPs, which for devices is 21 CFR 820.

Higher risk devices must be reviewed by the FDA prior to commercial sale in the US.  Class II devices generally are cleared by the FDA through the 510(k) review process, which focuses on “substantial equivalence” to a previously cleared and currently marketed “predicate device”.  Rarely are clinical trials required for 510(k)s. Clearance by the FDA allows the product to be marketed in the US.

If clinical trials are required for some Class II devices, they can sometimes by addressed only by hospital IRBs (Institutional Review Boards).  If the trial is necessary for new, novel Indications for Use, then the FDA needs to be involved prior to the clinicals.  This is done by a Q-Submission, to start a dialog with the FDA about the route to market for the proposed device, and/or an IDE (Investigational Device Exemption) submission to the FDA to allow the manufacture, shipment and clinical use of a somewhat experimental (investigational) device.     

The U.S. FDA mandates that the "Traditional" 510(k) submission address 21 basic requirements.  The "Special" and "Abbreviated" 510(k)s must also address them, but in different ways, e.g., ties to an existing 510(k) or certification to adherence to consensus standard(s).  In addition, the FDA Task Force has identified several problem areas with the existing medical device 510(k) process, leading to the growing push by the Agency to broaden the usage of the 510(k) process, under “Breakthrough Devices” (newer technology) or the STeP (new safety features) programs. Access to these newer programs is through the Q-Sub.

If a device is higher risk. It won’t be listed in the 21 CFR 800-series.  In such a case, it may be submitted to the FDA under a request for consideration as De Novo (a lower risk class III, possibly Class II, device).  If higher risk, definitely Class III, it will be submitted under the PMA (Pre-Market Approval) process.  Extensive clinical trials will be involved, and the process can take a couple of years or more (the 510(k) process generally is completed in about a half year).  Both the De Novo and PMA can benefit with initial dialog with the Agency via the Q-Sub.   Approval by the FDA allows the product to be marketed in the US.  The De Novo pathway results in the product subsequently being addressed under the 510(k) program.  Class III devices approved under the PMA program still require similar future products to also be reviewed under the PMA program.

-- jel@jelincoln.com