―Spotting Inadequate Investigations,
Corrective Actions, and
Overall Weak Quality/GMP Systems‖
Robert D. Seltzer
1
My Mantra
I.
Don‘t reinvent the wheel: use other people‘s wheels & axles.
II.
Use technical terms, acronyms, & abbrevs; but first define them.
III.
Learn, use, and keep learning (i) rules of logic, (ii) statistics,
(iii) quality tools.
IV.
Use profound quotes, clichés, analogies, metaphors, and imagery to
convey thoughts quickly
V.
Question assumptions, particularly long-held and cherished ones.
VI.
Be willing to tell the emperor/empress (s)he has no clothes.
VII.
Don‘t tell me, ―Choose your battles‖: it‘s guerilla war w/ snipers!
VIII. Ask anybody any question (except rhetorical ones—they insult!)
IX.
2
Jolt people‘s creativity via over-the-top humor. Note: read the book
by Roger von Oech‘ A Whack on the Side of the Head.
―If I have seen further than others, it is
by standing upon the shoulders of
giants.‖ –Sir Isaac Newton
3
Outline
I.
Truisms and Fallacies
II.
Triggers for Investigation, Remediation, and
Corrective Action
III. Risk Categorized and Semi-Quantified
IV. Causes and Effects & Tools for Better Investigation
V.
Corrective Action Completeness and Effectiveness
VI. GMP/Quality Maturity Models
4
I. Truisms and Fallacies
Good Definition: description of a word or multi-word
term that:
a) does not use any form of the word itself;
b) first places the word/term in a category or genus;
c) distinguishes the word sufficiently from other
category/genus members; and
d) satisfactorily describes the word for any Englishspeaking audience
5
I. Truisms and Fallacies
Working Definition: a satisfactory
description of a word/term for use with a
very specific audience, which differs from
the definition found in a customary English
dictionary
6
I. Truisms and Fallacies
Familiarity w/ applicable working def’ns means that:
• Technical discussions are facilitated;
• Jargon, acronyms, etc., when understood by all
present, shortens people’s sentences;
• Definitions can, in and of themselves, enable better
conceptualization and inherently organizes people’s
thoughts.
7
I. Truisms and Fallacies
Raw Data: any laboratory worksheets, records, memoranda, notes, or
exact copies thereof, that are the result of original observations and
activities of a non-clinical laboratory study [or any other activity such as
mf‘g, qualification, or validation, etc.] and are necessary for the
reconstruction and evaluation of the report of that study [or output of the
specific activity]. In the event that exact transcripts of raw data have
been prepared (e.g., tapes which have been transcribed verbatim,
dated, and verified accurate by signature), the exact copy or exact
transcript may be substituted for the original source as raw data. Raw
data may include photographs, microfilm or microfiche copies, computer
printouts, magnetic media, including dictated observations, and recorded
data from automated instruments.‖ --21CFR 58 GLPs
Note: Universally, color-photocopied, color-scanned, or color-faxed
versions of original documents are exact copies and, therefore, identical
raw data to the original.
8
I. Truisms and Fallacies
Note: Requirements, statements and definitions in seemingly inapplicable Parts of
Title 21 of the CFR are expected to be ―borrowed‖ / emulated by manufacturers
falling under other specific 21CFR Parts and product types (i.e., pharmaceutics Part
210-211; devices Part 820; dietary supplements Part 111; foods Part 110).
For example:
21CFR 820 Quality System Regulation for Medical Devices clearly defines and
describes/specifies Quality Audit (820.3)—Quality audit: a systematic, independent
examination of a manufacturer's quality system that is performed at defined intervals and
at sufficient frequency to determine whether both quality system activities and the results
of such activities comply with quality system procedures, that these procedures are
implemented effectively, and that these procedures are suitable to achieve quality
system objectives.
21CFR 58 clearly defines Raw Data (58.31) per previous slide.
21 CFR 11 clearly defines digital, handwritten signatures, and electronic records.
9
I. Truisms and Fallacies
Objective Evidence: bias-free physical, documentary, analytical, or
testimonial raw data gathered by an investigator(s), auditor, or
investigation team to support a conclusion (could be an audit finding
or inspection observation)
Note: ―Evidence‖ is generally defined as data (whether or not raw)
that is admissible in court.
10
I. Truisms and Fallacies
Common Sense: identical technical, subject matter, or procedural knowledge
possessed by all persons under discussion; if the knowledge is not shared by all
persons under discussion, it is ―divergent knowledge‖—not ―common sense.‖
Note: ―Common Sense‖ is often used as a popular label and way to explain why
others do not ―see‖ things the way we do and then criticizing or punishing them for it.
That is, some people label others as lacking common sense if not thinking or acting
according to our preconceived ideas. Therefore, ―Common Sense‖ is a fallacy!
Fallacy (common dictionary def‘n):
1. a deceptive, misleading, or false notion, belief, etc. (e.g., ―The world is flat.‖ was at
one time a popular fallacy)
2. a misleading or unsound argument
3. deceptive, misleading, or false nature; erroneousness
4. any of various types of erroneous reasoning that render arguments logically
unsound
―Whoever undertakes to set himself up as the judge of Truth and
Knowledge is shipwrecked by the laughter of the gods.‖ --Albert Einstein
11
I. Truisms and Fallacies
Continuous Improvement is a Misnomer!
Continual Improvement: An enhancement or upgrade that recurs in spurts and
stops (i.e., with interruption versus w/o interruption as in ―continuous‖).
Note: Kaizen is workforce-encouraged, undisciplined continuous improvement.
Change
Trigger Events: See first slide in Section
II
Continual
(often preventive action
sometimes corrective action)
Continuous
(uncontrolled, untested,
improperly conceived
change & NEVER how
preventive action or corrective
should occur)
Time
12
Discontinuity is essential to ensure that gains are consolidated and locked in!
II. Triggers for Investigation, Remediation, and Corrective Action
Trigger Events Best Defined by Examples Below:
 Periodic Product Review (e.g., Annual Product Review)
 Management Review (or Quality Council Meetings/Action Items)
 Change Control/ Change Request
 Atypical/ Out of Trend Result
 Out of Specification (analytical lab, micro lab, Envmt’l Limits)
 Notice of Event; Deviation; Variance (other degrees & synonyms)
 Nonconforming Material (incoming or in-process)
 Audit; Self-Inspection; Regulatory Inspection
 Product Quality Complaint
 Adverse Drug Reaction
 Unplanned/ Unscheduled Work Order
 Product Pre-Recall-or-Withdrawal Investigation
13
II. Triggers for Investigation, Remediation, and Corrective Action
Competent Authority: a country-specific agency or body designated to
administer that country‘s laws/statutes governing the marketing, manufacturing,
testing, and holding of safe and effective pharmaceuticals, medical devices,
foods, dietary supplements, cosmetics, etc. Note: examples include the US
Food and Drug Administration (FDA), Japan‘s Ministry of Health, Labor, and
Welfare (MHLW), Australia‘s Therapeutic Goods Administration (TGA).
Noncompliance: act, state, or result that violates a competent authority‘s
written or implied law, directive, regulation, or guidance/guideline
Deviation, Nonconformity, Variance (or any other synonym):
a departure from SOPs, methods, specifications, protocols, or other official
documentation; may also be a departure from instructions, process
specifications, or normal conditions (e.g., borderline conformances);
Note: Deviations are recorded either within a document such as a batch record
or validation report or in a stand-alone deviation record or in a database directly
(latter is ideal).
14
II. Triggers for Investigation, Remediation, and Corrective Action
Product Incident: an event or finding that might affect products in terms of
quality, safety, marketability, or viability within the company portfolio, such as
product complaint, product recall, market withdrawal, negative publicity, or a
directive from a competent authority
Product Quality Complaint: any communication, after a product is released
for distribution, that contains any allegation, written, electronic, or oral,
expressing concern, for any reason, with the quality of a product, that could be
related to current good manufacturing practice. Examples of product complaints
are: Foul odor, off taste, illness or injury, disintegration time, color variation,
tablet size or size variation, under-filled container, foreign material in a dietary
supplement container, improper packaging, mislabeling, or products that are
super-potent, sub-potent, or contain the wrong ingredient, or contain a drug or
other contaminant (e.g., bacteria, pesticide, mycotoxin, glass, lead)
Note: The above definition of Complaint borrows from both 21CFR 211
(finished pharmaceuticals) and 111 (dietary supplements).
15
II. Triggers for Investigation, Remediation, and Corrective Action
Two Powerful FDA Finished Drug CGMP Requirements around Investigations
21CFR 211.192 ―…Any unexplained discrepancy (including a
percentage of theoretical yield exceeding the maximum or minimum
percentages established in master production and control records) or
the failure of a batch or any of its components to meet any of its
specifications shall be thoroughly investigated, whether or not the
batch has already been distributed. The investigation shall extend to
other batches of the same drug product and other drug products that
may have been associated with the specific failure or discrepancy. A
written record of the investigation shall be made and shall include the
conclusions and follow-up.‖
21CFR 211.198 (b) (3) ―Where an investigation under 211.192 is not
conducted, the written record shall include the reason that an
investigation was found not to be necessary and the name of the
responsible person making such a determination.‖
16
II. Triggers for Investigation, Remediation, and Corrective Action
Necessary: of or having to do with a condition (in logic)
that must be met for the parent statement containing that condition
to have a possibility of truth
Sufficient: of or having to do with a condition (in logic) that, if met,
ensures the truth of the overall parent statement
Note: A condition can be either (1) necessary or (2) sufficient
without being the other. Lastly, a condition can be (3) both
necessary and sufficient.
Examples given on next slide:
17
II. Triggers for Investigation, Remediation, and Corrective Action
Example of Only Necessary
Manufacturing acetylsalicylic acid from non-animal is necessary but not sufficient for an
Aspirin product to be free of animal-spread pathogens, e.g., TSE.
Necessary: The finished drug must be manufactured using certifiably non-animal-origin
active pharmaceutical ingredient (API) acetylsalicylic acid.
Not sufficient: API freedom from animal origin material is necessary but not sufficient
for the finished drug to be free of animal-spread pathogens. For example, if gelatin is
used as an excipient and is derived from a herd of UK sheep, this weak link (esp for
TSE) negates all other measures.
Example of only Sufficient
Because the polymerase chain reaction (PCR) assay on a random environmental
monitoring bacterial colony isolated from a toploading balance in the dispensing room
determined the species to be purely Bacillus cereus, it is sufficient to conclude that a
Gram Positive spore former contamination has occurred in that area.
Sufficient: Organism identified via PCR ensures/guarantees this conclusion.
Not Necessary: Having to use this highly sensitive confirmatory genotypic assay at an
environmental monitoring investigation on a non-sterile, early mf‘g step is not
necessary (cheaper, phenotypic ID would prove bacillus contamination, e.g., Vitek or
characteristic colonies grown on Polymixin egg yolk selective agar).
18
II. Triggers for Investigation, Remediation, and Corrective Action
Example of Necessary and Sufficient Conditions Both Met
Statement: If the Quality Assurance Unit signs off and releases a particular lot of
finished pharmaceutical, then one can consider this lot to have been prepared
according to GMPs and not adulterated or misbranded.
Necessary: QAU‘s approval and sign-off is required for distribution of the finished
pharmaceutical.
Sufficient: QAU‘s approval and sign-off ensures/guarantees that no known or
unacceptable GMP violation, failure of specifications, or failure of required
environmental conditions, adulteration, or misbranding occurred to or during this lot.
The condition of QAU sign-off is necessary and sufficient for that conclusion.
―Logic will get you from A to B. Imagination will take you everywhere.‖
--Albert Einstein
19
IV. Causes and Effects & Tools for Better Investigation
How One Argentine Pharma Plant Triages Customer Communications into
Adverse Events & Complaints and Selects Appropriate Investigations/Tests
to Try to Understand the Causation System
20
II. Triggers for Investigation, Remediation, and Corrective Action
If the tracking (tickler file), trending, reviewing of triggers for investigations
or corrective actions is cumbersome or unsystematic, or a simple MS Word
or simple Excel spreadsheet (with no sorting), then:
a) Some instances of investigation and corrective action triggers might not be
recorded or assessed at all, not assessed properly, and/or not assessed in
a timely manner
b) Some investigations that should be performed consistently (because of
default questions and drop-down choices) wouldn‘t be consistent
c)
Regulatory or internal audits of trigger data or corrective actions would be
more difficult and prolonged
d) Many auditors and regulators would consider the absence of any database
to track, analyze, and trend investigation and corrective action trigger data
to be noncompliance with CGMPs
e) Beware the dependability of data/records and their traceability to date and
person creating or changing the record (Part 11)
21
II. Triggers for Investigation, Remediation, and Corrective Action
In this speaker’s opinion, the model CGMP database
for tracking, trending, and linking investigation and
corrective action triggers is
SPARTA Systems’ TrackWise®
See below references on the web
(I) Work Instruction by the European Medicines Agency (EMA)
for using TrackWise® EMA Work Instruction in TrackWise
http://www.emea.europa.eu/docs/en_GB/document_library/Work_Instruction__WINS/2009/09/WC500002711.pdf
(II) Applications of TrackWise® Enterprise Quality Management
http://www.spartasystems.com/trackwiseeqms/?utm_source=googlesearch&utm_medium=ppc_search&utm_campaign=g_tweqms_text_tosite&gclid
=CM2_gbTAqKYCFY9O4QodWj79Xw
22
III. Risk Categorized and Semi-Quantified
Risk: The perceived outcome of an event measured in terms of severity of
consequence and likelihood of occurrence of that event outcome
Risk Assessment: the determination of quantitative or qualitative value of
risk related to a hazard
Most risks relevant to GMP-related investigations fall within these categories:
Patient Health Risk
Product Conformance, Compliance, and/or Legal Risk
Process Risk
Reputational/Marketing/Market-Share Risk
Environmental, Transportation, or Worker Health Risk
23
III. Risk Categorized and Semi-Quantified
Examples of Ranks of 1 – 5 of Severity of Consequence
Score
Financial
5:
Catastro
-phic
Significant
operational
losses leading to
significant
reduction of
market value
Product
Quality
Severe
effect on
patient
health and
safety
Reputation
Regulatory
Environmental
Health & Safety
Fatality (ies) /
environmental
disaster resulting
Regulatory and
Govt intervention
(possible criminal
& civil charges,
and plant closure)
Legal
Extensive
national /
international
media scrutiny
and long-term
disruption of
stakeholder
confidence
Product
withdrawal or
non-approval of
blockbuster
product or
forced closure
of sole source
mf‘g plant.
Possible
criminal chrgs
Product
quality
unlikely to
affect pt
health and
safety
Short-term
local media
coverage and
disruption to
stakeholder
confidence
Fines and
penalties.
Operation
under consent
decree
Serious injuries /
some short-term
envir damage to
be remediated.
Regulatory minor
fines, penalties
Moderate
product
liability
litigation
Recoverable
interruption
to critical
activities in
short-term
(< 2 weeks)
Minimal impact to No effect
revenue or
on patient
earnings
health and
safety
Localized
annoyance/
concern/
complaints no
media
coverage
Reg warning
letter w/ fewer
issues,
products not
involving sig
health
consequences
Minor injuries /
negligible impact
on environment.
Incident reporting
according to
routine protocols
Legal
challenge
with minor
out-of-court
settlement
Impact can
be absorbed
within
normal
business
operations
Criminal
prosecution,
corp. and/or
execs fined
and possibly
imprisoned.
Nationwide
product
liability class
action
Business
Interruption
Recoverable
interruption
to critical
activities in
long-term
(greater
than 1
month)
4: Major
3:
Moderate
2:
Modest
1: Minor
24
Excessive costs
being incurred
that impact
current earnings
and profitability
III. Risk Categorized and Semi-Quantified
Examples of Ranks of 1 – 5 of Likelihood
Score
25
Description
1
Rare
2
Unlikely
3
Possible
4
Likely
5
Almost
certain
Examples
An incident might happen every 50 years
Incident might be seen once during working life.
Probability of incident close to zero
Controls are failsafe
An incident might happen every 5-10 years
May see several incidents during working life
Incident foreseeable but probability very low
Incident not known to have happened at another
business unit
An incident might happen every 1 - 5 years
An incident may have happened at another business unit
Controls may be breached
One or more incidents might occur a year
Personnel would not be surprised by incident
Significant number of incidents might occur each year
Incidents occur frequently
Control measures are not defined or are inadequate
III. Risk Categorized and Semi-Quantified
Consequence and Likelihood Matrix: table showing likelihood ranks down
the left side and consequence ranks across the top such that the two may be
multiplied to arrive at respective risk index values (RIVs)
Risk Index Value (RIV): The consequence score multiplied by the likelihood
score for an individual risk
26
III. Risk Categorized and Semi-Quantified
Risk Evaluation: The prioritization of identified and assessed risks
and determination of the risk-handling strategy
Note: Risk-handling strategies include (i) complete removal/
eradication of the confirmed causes, (2) mitigation, (3) improved
detection/ early warning, (4) no action but only monitoring.
However a strategy cannot be devised until the causation system is
understood.
27
IV. Causes and Effects & Tools for Better Investigation
Root Cause: The underlying reason for the actual or potential
occurrence of a non-conformity or other undesirable event outcome
The above definition represents
--and most of the GMP community believe—
that an undesirable event outcome has a single cause or
a linear, sequential set of causes.
28
IV. Causes and Effects & Tools for Better Investigation
Realitycharting was best introduced in the book by
Dean L. Gano called Apollo Root Cause Analysis.
Because Gano thought the concept of ―root cause‖ to
be at odds with his philosophy and method,
Realitycharting does not contain Root Cause Analysis
(RCA) in its name.
Gano postulates that causes and effects are really the
same thing, and they are part of an infinite continuum
(I’d call it a causation system). The complete
understanding of that causation system is limited
primarily by our lack of knowledge.
29
IV. Causes and Effects & Tools for Better Investigation
Realitycharting: a method described as follows: A team brainstorms
at least two causes (of the trigger event) in the form of an action and
condition along with evidence supporting those conditions. The team
then asks why of each stated cause until there are no more answers,
and produces a cause and effect chart that shows all the known causes
and their inter-relationships. All causes are then examined to find a way
to address them using a solution that is within the company‘s control,
prevents recurrence, and meets the company‘s goals and objectives.
30
IV. Causes and Effects & Tools for Better Investigation
Process repeats to create a
causation system (causeand-effect continuum)
31
IV. Causes and Effects & Tools for Better Investigation
Note: Brainstorming and decision-making to arrive at corrective action
solutions (sol‘ns) can use various tools such as the other so-called rootcause-analyses and force-field analysis—see below):
Force Field Analysis
Once the preferred corrective action tentatively selected, enter Driving Forces
supporting it as well as Restraining Forces to be overcome or minimized. Drivers
include justifications, resources/ people, business need(s), financial benefit(s),
risks reduced, etc.
Sample Corrective Action—(i) steam sanitize all formulation vessels used for solelyBenzalkonium-Chloride-preserved product and (ii) sterile filter all batching H2O.
DRIVING FORCES
32
RESTRAINING FORCES
Reduces to almost 0 the risk of
Burkholderia cepacia in product
Better product formulation w/ EDTA and
propylene glycol will make even cepacia unlikely
Additional preserving excipients cost
money and raise toxicity risks
USP-sourced EDTA and propylene glycol are
minimally toxic and exist in numerous drugs
This will reduce bioburden in unpreserved
products formulated in same vessels
Steam raises worker safety risks
IV. Causes and Effects & Tools for Better Investigation
The Fishbone isn’t an ―End All‖—Just one Brainstorm Aide!
33
IV. Causes and Effects & Tools for Better Investigation
The Five Why’s is Overly Simplistic!
"We can't solve problems by using the same kind of thinking we used when
we created them." --Albert Einstein
―If you do not know how to ask the right question, you discover nothing.‖
–W. Edwards Deming
34
IV. Causes and Effects & Tools for Better Investigation
What Impedes Understanding the Causation System
and Choosing the Optimal Corrective Action(s)?
Pessimism or negative expressions such as:
•
•
•
•
•
•
―It will never work here.‖ or ―No one will buy it.‖
―We already tried that once.‖
―It‘s not in the budget.‖
―Good thought, but impractical.‖
―No one else is doing it that way.‖
―We‘ve always done it that way.‖
Gano says not to let a solution-killing statement like these go
unanswered.
35
.
IV. Causes and Effects & Tools for Better Investigation
Gano counsels against adopting favorite solutions such as:
• Punish / Place a note in the person‘s HR file
• Reprimand
• Call it ―Human Error‖ as the Cause and Effect
• Retrain
• Put up a warning sign
• ―Ignore it—stuff happens.‖
Note: Read the book by Ferdinand F. Fournies: Why Employees Don‘t Do What
They‘re Supposed to Do…and What to Do about it
―When a system is stable, telling the worker about mistakes is only
tampering.‖ –W. Edwards Deming
Note: When workers are not in a state of self-control, per Joseph Juran‘s def‘n,
then the causation system points at management, and corrective actions must
be management‘s responsibility.
Joseph Juran’s Definition of an Operator Beining in state of self-control,:
•Must Know what the target is;
•Must have a means to measure performance;
36 •Must have the ability to take corrective action
IV. Causes and Effects & Tools for Better Investigation
Cynic: a person who believes that only selfishness motivates human actions
and who disbelieves in or minimizes selfless acts or disinterested points of
view.
―Cynicism masquerades as wisdom, but it is the farthest thing from it,
because cynics don’t learn anything, because cynicism is a self-imposed
blindness, a rejection of the world because we are afraid it will hurt us or
disappoint us. –Stephen Colbert
37
V. Corrective Action Completeness and Effectiveness
CAPA (corrective and preventive action) are not ―wedded‖
concepts.
Corrective Action: Activity or project to eliminate, mitigate, or
better detect some or all of the causes of a detected nonconformity or other undesirable situation, and thus avoid or
reduce recurrence.
Preventive Action: Activity or project to eliminate, mitigate, or
better detect some or all of the causes of a hitherto non-occurring
or unseen, but not improbable non-conformity or other
undesirable situation, and thus preclude or reduce the probability
of its occurrence.
―The time to repair the roof is when the sun is shining.‖
--John F. Kennedy
38
V. Corrective Action Completeness and Effectiveness
Remedial Action: Immediate measure(s) taken
to address an urgent and/or damaging trigger
event until a thorough investigation and a
corrective action is implemented
―Walter Shewhart conceptualized the ―Plan, Do,
Check, Act‖ cycle.
However, many practice only the second step, which
results in a ―Do Do‖ organization‖ –Anonymous
39
V. Corrective Action Completeness and Effectiveness
―If it ain’t broke, don’t fix it.‖ –possibly the
most dangerous, fallacious proverb of all
time! It‘s fittingly attributable to
T. Bert (Thomas Bertram) Lance, the Director
of the OMB in Jimmy Carter‗s administration.
40
V. Corrective Action Completeness and Effectiveness
Corrective Action Completeness is defined & achieved by the following:
1.
Necessary and sufficient training (or re-training) has been administered
(does rule exist of not more than 20% absentees from training?);
2.
Necessary and sufficient procedures, instructions, and/or physical changes
are ―in place‖ (i.e., written & issued, or installed & commissioned);
3.
Necessary and sufficient qualification, validation, and/or other implementation
(i.e., ―in use‖) has/have been confirmed by the site quality unit (SQU) and then
stated or recorded as such.
Note: Nothing in a key GMP procedure or expectation should be superfluous
(meaning, everything is necessary), AND there must be a minimum threshold of
adequate corrective action measures (i.e., the sum total of all necessary items create
sufficiency). Thus the reason for the ―necessary and sufficient‖ clause in all the
Completeness criteria.
41
Note: Corrective Action completeness
≠ effectiveness!
V. Corrective Action Completeness and Effectiveness
Corrective Action Effectiveness is defined and
achieved by most or all the following:
1.
The causation system of the trigger event‘s outcome have been identified
and have become better understood (e.g., using Realitycharting).
2.
Defensible, risk-based solution(s)/corrective action(s) has(have) been
determined and adopted controllably (e.g., via change control, vald‘n).
3.
Proper monitoring has been put in place around the implemented
corrective action(s).
4.
A determination has been made that corrective action(s) has/ have not
resulted in any other undesirable event outcomes as a by-product.
5.
From the determined causation system, the original trigger event‘s
outcome doesn‘t reappear (or to a lower frequency). This criterion will
likely require trending/databasing.
42
VI. GMP/Quality Maturity Models and Relevant Quotes
Quality Management Maturity Grid of Philip Crosby
43
VI. GMP/Quality Maturity Models
Spectrum of GMP & Quality Believers/Learners
(Like GE Jack Welch‘s 10% non-achieving, 70% highly achieving, & 20% super-achieving)
Incorrigible,
Non-Believing,
Untrainable
Initially
Easily
Skeptical,
Trainable,
then
Positively
Progressively
Impressionable
Trainable
A Zealot Devoted to
Quality, a Role Model,
a Trainer, a Sage
VI. GMP/Quality Maturity Models
Note: Companies / auditees who say,
―We look at findings as opportunities to
improve‖ are usually outstanding and are in
Yoda‘s company on the previous graph.
―A pessimist
sees the difficulty in every opportunity; an
optimist sees the opportunity in every difficulty.‖
–Sir Winston Churchill
45
VII. GMP/Quality Maturity Models
Example of an Audit Finding for Seriously Inadequate QC investigations at a US
Multinational API Plant in China:
Investigations around analytical results are not always complete or ask the appropriate
questions to enable the appropriate remedy(ies) or corrective action(s). Two out of two
OOSs were the sampling and rate of this discovery. Specifically:
a) Inv-OOS-TJ2-2009-08-02 reaches an unsupported conclusion for a raw material test
OOS result of 46.82 % content of chloromethyl methylester vs spec of greater than 99%
as being caused by storage deterioration of the sample. No conclusive, supporting study
was conducted to simulate and support this conclusion. Also the investigation does not
look into why it deteriorated. Additionally, a cross-functional investigation of the improper
storage was not conducted.
b) Inv-OOS-TJ2-2009-07-02 for a GC result of 2.2% versus a spec of < 0.5% for an API.
The samples from the packaged drum had heterogeneities of chunks and powder of
MTBE (methyl tributyl methyl ether). The CAPA addresses the drying process but not the
reason why QC accepted the sample for analysis based on its questionable appearance.
No appearance specification currently exists for this API.
The risk is that proper remedies and corrective actions will not be taken in
response to material test failures and the site will face the same failure repeatedly.
46
VII. GMP/Quality Maturity Models
Example of FDA Warning Letter Item for a US
Contract Parenteral Drug Manufacturer
―There was a failure to thoroughly investigate any unexplained
discrepancy or the failure of a batch or any of its components to
meet any of its specifications whether or not the batch has
already been distributed [21 C.F.R. § 211.192]. For example:
a. Your firm did not conduct a thorough investigation to
determine the source of endotoxin contamination.
(1) Your firm failed to conduct thorough investigations into the
failure of multiple lots of Propofol (958302, 958364, 958438,
958445, and 968716) that significantly exceeded in-process
levels for endotoxin ([redacted] EU/ml) during [redacted]
testing, but later passed final product testing for endotoxin.
Your quality control unit (QCU) determined these lots to be
acceptable for release without determining the source of the
contamination.
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VII. GMP/Quality Maturity Models
Example of FDA Warning Letter Item for a US Contract Parenteral Mf’r (cont’d)
(2) Your investigation of these lots concluded that since the inprocess test for endotoxin was for investigational purposes, full
investigations were not required. A root cause for the high
[redacted] results for endotoxin was not identified, and the
results were not scientifically invalidated by any of your firm's
investigations.
In light of the high endotoxin test results seen at your facility
during the manufacturing of Propofol, we are concerned that
your firm may lack an adequate understanding of the product
and the process for manufacturing Propofol. We strongly
recommend that your firm review your process design and
endotoxin controls for the entire manufacturing process, e.g.,
prior to the filtration and terminal sterilization. Some
considerations may include the raw materials used in the
process and the lengthy compounding process.
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VII. GMP/Quality Maturity Models
―Even if you’re on the right
track, you’ll get run over if you
just sit there.‖—Will Rogers
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