Identifying and Preventing the
Most Common Drug and Device
cGMP Issues
The FDA Group Presentation
Neal Siegel, Industry Quality/Regulatory Consultant
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Introduction
Neal A Brief Introduction
Siegel, • Independent Quality/Regulatory consultant
Ph.D. (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.
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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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Top 5-Year Cumulative Trending cGMP FDA
Inspectional Observation Citations (US)
Drug Device
1. 211.192 — Investigations of 1. 820.100(a) — CAPA (establishing and
discrepancies maintaining procedures)
2. 211.22(d) — Quality control unit 2. 820.198(a) — Complaint files
procedures
3. 820.90(a) — Control of nonconforming
3. 211.160(b) — Lab controls (should product
include scientifically sound
specifications) 4. 820.75(a) — Process validation
4. 211.100(a) — Written procedures for
production and process controls
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Drug
211.192 — Investigations of discrepancies
Observations from the field Considerations for review and enhancement
• Unclear or misused definitions ü Review to ensure you’re using accurate
prevent investigations from reaching definitions to steer investigations in the right
genuine root causes. direction.
• A lack of robust root cause analysis • “Is this a genuine nonconformance, or is it
methods. an out-of-specification or out-of-tolerance
issue to the measurement system?”
• “No or incomplete written record of
investigation” often indicates that ü Be clear and concise about what you're
data isn’t recorded properly. writing down.
• “Failure to investigate discrepancies, ü Investigate fully to know what's being looked
failures” often signals inadequate at. Investigate in a methodical manner
root cause investigation. without jumping to conclusions.
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Drug
211.192 — Investigations of discrepancies
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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Drug
211.192 — Investigations of discrepancies
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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Drug
211.192 — Investigations of discrepancies
Warning letter excerpt (2/2)
[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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Drug
211.22— Responsibilities of quality control unit
Observation from the field Considerations for review and enhancement
• Pressure from leadership and/or a ü Put “effective communication” into practice.
lack of communication and visibility
into Quality metrics challenges • Make Quality data accessible and inviting
Quality’s responsibility to approve or for management via dashboards.
reject products. • 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.
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Drug
211.22— Responsibilities of quality control unit
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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Drug
211.160(b) — Lab controls (scientifically sound
specifications)
Observations from the field Considerations for review and enhancement
• Specifications: Specs are adopted ü Specifications: Strive to actively develop
more than they’re developed. specifications to exceed guideline specs if the
appropriate controls are in place.
• Standards: Standards aren’t
sufficiently traceable to national ü Standards: Make sure all standards used are
standards (and therefore can’t be traceable to a national standard.
fixed when they’re broken).
ü Test procedures: Make sure any test
• Test procedures: Insufficiently procedures modified from compendial
validated or compendial. methods are fully validated.
• Sampling plans: Sometimes these ü Sampling plans: Don’t deviate from
are deviated from. established sampling methods.
ü Understand if random sampling is called for.
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Drug
211.160(b) — Lab controls (scientifically sound
specifications)
Common potential red-flags of a larger quality system problem
ü A lack of management controls for reviewing data (signatures don’t signify
proper verification)
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Drug
211.160(b) — Lab controls (scientifically sound
specifications)
Warning letter excerpt (1/3)
“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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Drug
211.160(b) — Lab controls (scientifically sound
specifications)
Warning letter excerpt (2/3)
“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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Drug
211.160(b) — Lab controls (scientifically sound
specifications)
Warning letter excerpt (3/3)
• 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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Drug
211.100(a) — Written procedures for production
and process controls
Observations from the field Considerations for review and enhancement
• Imprecise instruction: Non- or ü Review SOPs for total prescriptiveness.
inadequately-prescriptive
procedures leave something for ü Regarding specifications, look at your
operators to interpret. validation for the process and replace any
single value requirements with the
• Single-value specifications: Single appropriate range that must be met.
values are impossible to pass.
ü Review procedures for proper conditional
• Lack of condition recording: Any recording, such as temperature readings, time
procedure requiring a condition be durations, etc.
met should ensure that condition is
recorded as a quantifiable value, not
simply ”checked.”
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Drug
211.100(a) — Written procedures for production
and process controls
Common potential red-flags of a larger quality system problem
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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Drug
211.100(a) — Written procedures for production
and process controls
Warning letter excerpt (1/2)
“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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Drug
211.100(a) — Written procedures for production
and process controls
Warning letter excerpt (2/2)
“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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Device
820.100(a) — CAPA (establishing and maintaining
procedures)
Observations from the field Considerations for review and enhancement
• Largely the same observations ü Review CAPA logs and ask the important
discussed earlier with investigations questions.
and root cause.
• “Why are CAPAs aging this long?”
• Many investigations don’t result in a
• “Why aren’t the most resources going to
genuine root cause, which is key to
the oldest CAPAs?”
prevention.
• “Are issues we’re seeing with the log due
• Upper management doesn’t provide to extenuating circumstances specific to
the appropriate amount of personnel the problem, or is it a resourcing issue?”
to Quality to get things done.
ü Management must offer the resources to
ensure there are enough staff to conduct
Quality investigations.
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Device
820.100(a) — CAPA (establishing and maintaining
procedures)
Common potential red-flags of a larger quality system problem
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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Device
820.100(a) — CAPA (establishing and maintaining
procedures)
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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Device
820.198(a) — Complaint files
Observations from the field Considerations for review and enhancement
• “Inadequate complaints procedures” ü Make sure there’s regular communication with
often indicates an investigation purchasing regarding complaints if
problem. Does Quality know a complaints are received there first.
complaint was received?
ü Make sure Quality is deciding which
• Quality teams sometimes don’t have complaints are “valid” complaints and acting
the information they need to make on them accordingly.
informed decisions for categorizing
and investigating complaints ü Review complaint collection processes or
appropriately. This is usually a documentation to ensure Quality has the
collection problem. information it needs to manage complaints.
• When “complaint files are not or not ü As required, always keep complaint files
adequately maintained,” the problem accessible and make sure complaints that
often lies in the handling of result in injury or death are managed
complaints that result in injury or separately.
death.
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Device
820.198(a) — Complaint files
Common potential red-flags of a larger quality system problem
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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Device
820.198(a) — Complaint files
Warning letter excerpt (1/2)
“...[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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Device
820.198(a) — Complaint files
Warning letter excerpt (2/2)
“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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Device
820.90(a) — Control of nonconforming product
Observations from the field Considerations for review and enhancement
• Improper control leads to some ü Whether or not a product can be reworked
manner of releasing nonconforming based on its disposition, it must be always
products. controlled.
• Absent or inadequate root cause ü Nonconformances must be fully investigated,
investigations into and the result of that investigation should
nonconformances. Was it the determine whether a CAPA is required.
product or the operation around it?
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Device
820.90(a) — Control of nonconforming product
Common potential red-flags of a larger quality system problem
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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Device
820.90(a) — Control of nonconforming product
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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Device
820.75 — Process validation
Observations from the field Considerations for review and enhancement
• Process validation is being handled ü Carefully review FDA guidance and warning
as an engineering function. letters to understand regulators’ expectations
for process validation.
• Lack of scientific judgement is being
applied to answer critical questions Let’s look at one now…
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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Device
820.75 — Process validation
Warning letter excerpts
“a. Your firm’s validated cleaning process is not routinely monitored to assess contamination levels
for 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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Device
820.75 — Process validation
Warning letter excerpts
“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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Device
820.75 — Process validation
Warning letter excerpts
“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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Wrapping Up:
Key Questions to Consider
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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