Identifying and Preventing the Most Common Drug and Device ...

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The FDA Group PresentationNeal Siegel, Industry Quality/Regulatory Consultant

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IdentifyingandPreventingtheMostCommonDrugandDevice

cGMPIssues

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A Brief Introduction

• Independent Quality/Regulatory consultant (IVD/Med Device/Pharma) with 25+ years of experience and a particular interest in quality statistics and understandable, practical application in instances of compliance shortcomings.

• Extensive, successful experience from lab bench to C-suite. Participated on assessment and remediation teams for companies with severe Warning Letters and Consent Decrees and is knowledgeable in successful recovery from these types of regulatory actions.

Introduction

Neal Siegel, Ph.D.

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Agenda

1. Discuss four commonly observed issues relating to top trending drug GMP issues

2. Discuss four commonly observed issues relating to top trending device GMP issues

3. Q&A

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Top5-YearCumulativeTrendingcGMPFDAInspectionalObservationCitations(US)

Drug

1. 211.192 — Investigations of discrepancies

2. 211.22(d) — Quality control unit procedures

3. 211.160(b) — Lab controls (should include scientifically sound specifications)

4. 211.100(a) — Written procedures for production and process controls

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Device

1. 820.100(a) — CAPA (establishing and maintaining procedures)

2. 820.198(a) — Complaint files

3. 820.90(a) — Control of nonconforming product

4. 820.75(a) — Process validation


Drug211.192— Investigationsofdiscrepancies

Observations from the field

• Unclear or misused definitions prevent investigations from reaching genuine root causes.

• A lack of robust root cause analysis methods.

• “No or incomplete written record of investigation” often indicates that data isn’t recorded properly.

• “Failure to investigate discrepancies, failures” often signals inadequate root cause investigation.

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Considerations for review and enhancement

ü Review to ensure you’re using accurate definitions to steer investigations in the right direction.

• “Is this a genuine nonconformance, or is it an out-of-specification or out-of-tolerance issue to the measurement system?”

ü Be clear and concise about what you're writing down.

ü Investigate fully to know what's being looked at. Investigate in a methodical manner without jumping to conclusions.



Common red-flags of a larger quality system problem

ü Root causes are not determined, or unclear

ü Root causes are often identified as ”mistakes” or similarly shallow terms

ü Root causes are unrelated to the observations (due to, perhaps, improper categorization)

ü Indications that someone isn’t reading what they’re signing

ü Improper use of statistics

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Warning letter excerpt (1/2)

“Your investigations were not thorough and did not fully address non-conforming products on the market. You failed to adequately investigate the stability of your [product] after complaints about product odors. You determined that the root cause of the atypical odors was a reaction of [substance] with improperly cured containers. However, the CAPA you implemented were inadequate: you concluded that the product was safe although it may not remain stable over its shelf-life. You failed to recall these products.”

“In your response, you said that the product owner performed a toxicological study of the defective product and found it did not pose risks. Your response was inadequate. You did not evaluate all product lots for stability in this reactive container-closure system to ensure it would meet all specifications over its shelf-life, including but not limited to assay and impurity profile.”

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[Requests]

• Data to show that your [product] is stable over the intended shelf-life, and an action plan to address any nonconforming products still in distribution, including potential recalls or market withdrawals.

• A comprehensive, independent assessment of your system for investigating deviations, atypical events, complaints, OOS results, and failures. Your CAPA plan should include, but not be limited to, improvements in investigations, root cause analysis, written procedures, and quality unit oversight. Also include your process for evaluating CAPA plan effectiveness.

• A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are qualified and assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable containers, closures, and components.

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Drug211.22— Responsibilitiesofqualitycontrolunit

Observation from the field

• Pressure from leadership and/or a lack of communication and visibility into Quality metrics challenges Quality’s responsibility to approve or reject products.

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ü Put “effective communication” into practice.

• Make Quality data accessible and inviting for management via dashboards.

• Schedule regular check-ins/reviews where recent observations can be compared against trending issues.

ü Use statistical process control appropriately.

• This is an incredibly useful tool for spotting and responding to issues when they occur before they become a larger and more expensive problem.


Drug211.22— Responsibilitiesofqualitycontrolunit

Common potential red-flags of a larger quality system problem

ü A lack of active communication leads to avoidable surprises

ü A lack of investment in tools like SPC

ü Output from SPC fails to turn into insights that can be acted upon

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Drug211.160(b)— Labcontrols(scientificallysoundspecifications)


• Specifications: Specs are adopted more than they’re developed.

• Standards: Standards aren’t sufficiently traceable to national standards (and therefore can’t be fixed when they’re broken).

• Test procedures: Insufficiently validated or compendial.

• Sampling plans: Sometimes these are deviated from.

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ü Specifications: Strive to actively develop specifications to exceed guideline specs if the appropriate controls are in place.

ü Standards: Make sure all standards used are traceable to a national standard.

ü Test procedures: Make sure any test procedures modified from compendial methods are fully validated.

ü Sampling plans: Don’t deviate from established sampling methods.

ü Understand if random sampling is called for.




ü A lack of management controls for reviewing data (signatures don’t signify proper verification)

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“Your laboratory sampling plans and testing methods were not scientifically sound. You collected non-representative samples of your (b)(4) water system. Your procedures specified collecting samples from the (b)(4) of the (b)(4) water system. However, our inspection found that you used purified water stored in plastic containers held in ambient conditions for manufacturing. The sampling location should be the same as the point-of-use, and represent worst-case conditions. Note, however, that storing water in plastic containers for extended periods of time may also pose a significant hazard for microbial contamination”

“Furthermore, your microbiological test methods used for testing water and/or finished products were deficient:

• You lacked growth promotion testing for your microbiological media.

• You lacked method suitability.

• Your microbiological testing procedures lacked sufficient details to establish how many units in the finished product batch are to be used for microbiological testing.”

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“In your response, you stated that you revised your procedures to include suitability of test media and that you will perform suitability tests (b)(4). Your response is inadequate because suitability testing should be performed on every lot of media, due to potential lot-to-lot variation in media preparation. Furthermore, your response was also inadequate because it did not address the effects of your deficient laboratory practices on drug products on the market within expiry.

In your response to this letter, provide:

• An independent assessment of all test methods used by your firm to ensure they have appropriate instructions, method suitability criteria, and appropriate validation (or verification, for USP compendial methods) to determine whether they are fit for their intended use.

• Your plan of action to complete validation (or verification, for USP compendial methods) for all analytical test methods.

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• A comprehensive independent review of your entire laboratory system, and a CAPA plan that ensures full remediation of the laboratory operation. For example, the review of your laboratory system should include, but not be limited to, the suitability of all laboratory equipment and methods, a fully remediated calibration program, staff competencies, supervisory oversight, data systems, and other elements of laboratory control, such as sampling.

• Details on whether you pool or mix the product to make the testing sample.”

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Drug211.100(a)—Writtenproceduresforproductionandprocesscontrols


• Imprecise instruction: Non- or inadequately-prescriptive procedures leave something for operators to interpret.

• Single-value specifications: Single values are impossible to pass.

• Lack of condition recording: Any procedure requiring a condition be met should ensure that condition is recorded as a quantifiable value, not simply ”checked.”

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ü Review SOPs for total prescriptiveness.

ü Regarding specifications, look at your validation for the process and replace any single value requirements with the appropriate range that must be met.

ü Review procedures for proper conditional recording, such as temperature readings, time durations, etc.




ü Procedures that are found not to match the the validated process requirements

ü A lack of critical quality attributes or key process parameters associated with a given process

ü Unused forms are included in procedures

ü Older versions of procedures are found at the workstation

ü Other examples of a lack of good documentation practices

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“You failed to validate your processes and qualify equipment used to manufacture your (b)(4) drug products. Specifically, you did not perform process qualification studies, nor did you have a rigorous ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.”

“In your response, you committed to pursuing an improved process validation program for new drug products, to assess the manufacturing processes for existing products, and to qualify your current and future manufacturing equipment. However, you failed to provide assurance that your manufacturing equipment is suitable for its intended uses and that your manufacturing processes are reproducible and capable of meeting all predetermined quality attributes.”

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“In response to this letter, provide the following.

• A validation plan for ensuring a state of control throughout the product lifecycle. Include a timeline for performing appropriate process performance qualification (PPQ) for each of your drug products. Describe your program for monitoring batch-to-batch variation to ensure an ongoing state of control.

• The process performance protocols and studies that evaluate whether your manufacturing equipment and processes are reliable. This includes but is not limited to determining whether your production parameters are consistently met and whether your process is capable of reproducibly yielding a product that meets its quality attributes.”

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Device820.100(a)— CAPA(establishingandmaintainingprocedures)


• Largely the same observations discussed earlier with investigations and root cause.

• Many investigations don’t result in a genuine root cause, which is key to prevention.

• Upper management doesn’t provide the appropriate amount of personnel to Quality to get things done.

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ü Review CAPA logs and ask the important questions.

• “Why are CAPAs aging this long?”

• “Why aren’t the most resources going to the oldest CAPAs?”

• “Are issues we’re seeing with the log due to extenuating circumstances specific to the problem, or is it a resourcing issue?”

ü Management must offer the resources to ensure there are enough staff to conduct Quality investigations.




ü Aging CAPA logs often indicate an under-staffed unit

ü A lack of cross-functionality in conducting investigations and root cause analysis; identifying incorrect root cause.

ü A lack of capability to track and respond to trending issues

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Warning letter excerpt

“Your firm has not established procedures for implementing corrective and preventive actions. CAPA procedures must be established and followed in the event a nonconforming product and other quality problems are found.”

“We reviewed your firm’s response and conclude it is not adequate. You indicated your Continual Improvement procedure (BSP-14) outlines the process for documenting corrective and preventive actions. However, your Corrective Action Request (CAR) form was not included to verify all CAPA activities have been documented. Also, as per your response letter (dtd. 11/28/18), there are no training records to demonstrate the employees have attended an online course to understand the CAPA process.”

“response to the Warning Letter, we request you provide examples of your Corrective Action Request forms which would demonstrate the process is documented and all activities under this section, and their results, have been implemented.”

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Device820.198(a)— Complaintfiles


• “Inadequate complaints procedures” often indicates an investigation problem. Does Quality know a complaint was received?

• Quality teams sometimes don’t have the information they need to make informed decisions for categorizing and investigating complaints appropriately. This is usually a collection problem.

• When “complaint files are not or not adequately maintained,” the problem often lies in the handling of complaints that result in injury or death.

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ü Make sure there’s regular communication with purchasing regarding complaints if complaints are received there first.

ü Make sure Quality is deciding which complaints are “valid” complaints and acting on them accordingly.

ü Review complaint collection processes or documentation to ensure Quality has the information it needs to manage complaints.

ü As required, always keep complaint files accessible and make sure complaints that result in injury or death are managed separately.


Device820.198(a)—Complaintfiles


ü Complaint backlogs (due to an under-resourced unit or long wait times for cross-functional input)

ü Chronic intake issues

ü Improper complaint categorization

ü Issues stemming from inadequate or incomplete service records

ü Issues stemming from inadequate training for risk assignment and ranking

ü Investigations of complaints that don’t extend back to manufacturing

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Device820.198(a)— Complaintfiles


“...[company] received a complaint from [customer company] about observed negative bias in test results obtained from [customer company]’s devices when using blood collected in [company’s product]. Your firm did not enter this information into its complaint system, evaluate the complaint to determine if it represents an MDR reportable event, or initiate an investigation of the complaint.”

“[section of company SOP] fails to identify the (b)(4) inquiry call log as a source of data for complaint review. Additionally, (b)(4) audits of this log by the technical service department failed to evaluate and identify entries as product complaints and to evaluate them for potential MDR reportability.“

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Device820.198(a)—Complaintfiles


“During the inspection, your firm’s World Wide Vice President for Quality Management explained that your firm has no written procedures for the use of [redacted reporting software]. This software, which has been used by your sales representatives since 12/2014, and is used for documenting and reporting complaints and product incident reports. The (b)(4) software is also used in collecting information for potential device complaints, malfunctions and MDR reportable events.”

“We … acknowledge that your [prior] response states that your firm will conduct a retrospective review of complaints, and will make additional revisions to its MDR procedure. However, your firm’s response did not include all of the completed documentation to support these corrections and corrective actions.”

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Device820.90(a)— Controlofnonconformingproduct


• Improper control leads to some manner of releasing nonconforming products.

• Absent or inadequate root cause investigations into nonconformances. Was it the product or the operation around it?

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ü Whether or not a product can be reworked based on its disposition, it must be always controlled.

ü Nonconformances must be fully investigated, and the result of that investigation should determine whether a CAPA is required.




ü Nonconformances aren’t being (fully) investigated

ü Root causes for nonconformances aren’t being identified or misidentified

ü Chronic nonconformity issues aren’t being proactively addressed

ü Nonconforming product is being released or not fully controlled disposition

ü Mock recalls are not performed

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Warning letter excerpt

“[product, lot [lot number] was reworked in 2015. The [products] failed endotoxin testing but were released and distributed.

“Your firm’s [prior responses] are not adequate. In your firm’s responses, it noted that you have recalled all items mentioned in [relevant observation]. While you submitted a recall for [another product issue], this recall did not include [impacted lot] for [observed issue], which was referenced in [company technical bulletin].”

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Device820.75— Processvalidation


• Process validation is being handled as an engineering function.

• Lack of scientific judgement is being applied to answer critical questions like, what should you measure? How should you measure it? How should you establish specifications used for the process validation?

• Lack of rigor applied to establishing critical quality attributes or “objective evidence.”

• A lack of training documented in validation.

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ü Carefully review FDA guidance and warning letters to understand regulators’ expectations for process validation.

Let’s look at one now…



Warning letter excerpts

“a. Your firm’s validated cleaning process is not routinely monitored to assess contamination levelsfor reprocessed single-use devices subjected to the process. The most recent assessments for contamination were performed in 2012 as part of Cleaning Validation of Compressed Sleeves, Protocol #12019 (for hemoglobin and bioburden) and Cleaning Validation of Orthopedic, ENT and Laparoscopic Instruments, Protocol #12020-A (for hemoglobin and protein). However, your firm’s procedure, titled QAP008-Appendix C, Validation of Product, Equipment and Process for EO Sterilization, Rev. 1, states, “Product bioburden is controlled through the cleaning process and monitored on a quarterly basis…;.” No documented evidence was provided during the current inspection to support this requirement as required by your procedures.”

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“b. Your firm has failed to adequately identify the worst-case product used during the validation of your firm’s sterilization process. The 2014 and 2013 Performance Qualification of Sterilization Process reports both state under item #2 that “the (b)(4) devices within the load would present a bioburden challenge”. During our review of sterilization records, Sterilization Batch Record (SBR) #782 indicated that (b)(4) devices were sterilized in that load, with over (b)(4) more devices than used in the validations.”

“c. The numbers of samples chosen for use in the Cleaning Validation studies were not based on a valid statistical technique.”

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“b. Your firm has failed to adequately identify the worst-case product used during the validation of your firm’s sterilization process. The 2014 and 2013 Performance Qualification of Sterilization Process reports both state under item #2 that “the (b)(4) devices within the load would present a bioburden challenge”. During our review of sterilization records, Sterilization Batch Record (SBR) #782 indicated that (b)(4) devices were sterilized in that load, with over (b)(4) more devices than used in the validations.”

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WrappingUp:KeyQuestionstoConsider

q [Question 1] — Are investigations thorough enough to correctly identify the root cause?

q [Question 2] — Are review signatures confirming that the data, procedures and associated information are correct and current?

q [Question 3] — Are metrics assessing the effectiveness of the Quality Control Unit in place and effectively used by Management?

q [Question 4] — Are nonconforming products controlled, documented and appropriately dispositioned?

q [Question 5] — Are limits specified by Qualifications and Validations met by procedures?

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Q&A

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Identifying and Preventing the Most Common Drug and Device ...

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