Spotting Inadequate Investigations, Corrective Actions ... · 1 ―Spotting Inadequate...

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1 Spotting Inadequate Investigations, Corrective Actions, and Overall Weak Quality/GMP Systems‖ Robert D. Seltzer

Transcript of Spotting Inadequate Investigations, Corrective Actions ... · 1 ―Spotting Inadequate...

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―Spotting Inadequate Investigations, Corrective Actions, and

Overall Weak Quality/GMP Systems‖

Robert D. Seltzer

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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. 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.

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―If I have seen further than others, it is

by standing upon the shoulders of

giants.‖ –Sir Isaac Newton

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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

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I. Truisms and Fallacies

Good Definition: description of a word or multi-wordterm 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 English-speaking audience

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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

I. Truisms and Fallacies

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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.

I. Truisms and Fallacies

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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.

I. Truisms and Fallacies

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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.

I. Truisms and Fallacies

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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.

I. Truisms and Fallacies

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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

I. Truisms and Fallacies

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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.

Continual Continuous

(often preventive action (uncontrolled, untested,

sometimes corrective action) improperly conceived

change & NEVER how

preventive action or corrective

should occur)

Discontinuity is essential to ensure that gains are consolidated and locked in!

Change

Time

I. Truisms and Fallacies

Trigger Events: See first slide in Section

II

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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

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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).

II. Triggers for Investigation, Remediation, and Corrective Action

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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).

II. Triggers for Investigation, Remediation, and Corrective Action

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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.‖

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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) bothnecessary and sufficient.

Examples given on next slide:

II. Triggers for Investigation, Remediation, and Corrective Action

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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).

II. Triggers for Investigation, Remediation, and Corrective Action

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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

II. Triggers for Investigation, Remediation, and Corrective Action

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IV. Causes and Effects & Tools for Better InvestigationHow One Argentine Pharma Plant Triages Customer Communications into

Adverse Events & Complaints and Selects Appropriate Investigations/Tests

to Try to Understand the Causation System

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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)

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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 TrackWisehttp://www.emea.europa.eu/docs/en_GB/document_library/Work_Instruction_-

_WINS/2009/09/WC500002711.pdf

(II) Applications of TrackWise® Enterprise Quality Managementhttp://www.spartasystems.com/trackwise-

eqms/?utm_source=googlesearch&utm_medium=ppc_search&utm_campaign=g_tweqms_text_tosite&gclid

=CM2_gbTAqKYCFY9O4QodWj79Xw

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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

III. Risk Categorized and Semi-Quantified

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Examples of Ranks of 1 – 5 of Severity of Consequence

Score Financial Product

Quality

Reputation Regulatory Environmental

Health & Safety

Legal Business

Interruption

5:

Catastro

-phic

Significant

operational

losses leading to

significant

reduction of

market value

Severe

effect on

patient

health and

safety

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

Fatality (ies) /

environmental

disaster resulting

Regulatory and

Govt intervention

(possible criminal

& civil charges,

and plant closure)

Criminal

prosecution,

corp. and/or

execs fined

and possibly

imprisoned.

Nationwide

product

liability class

action

Recoverable

interruption

to critical

activities in

long-term

(greater

than 1

month)

4: Major

3:

Moder-

ate

Excessive costs

being incurred

that impact

current earnings

and profitability

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)

2:

Modest

1: Minor Minimal impact to

revenue or

earnings

No effect

on patient

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

III. Risk Categorized and Semi-Quantified

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Examples of Ranks of 1 – 5 of Likelihood

Score Description Examples

1 Rare

An incident might happen every 50 years

Incident might be seen once during working life.

Probability of incident close to zero

Controls are failsafe

2 Unlikely

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

3 PossibleAn incident might happen every 1 - 5 years

An incident may have happened at another business unit

Controls may be breached

4 LikelyOne or more incidents might occur a year

Personnel would not be surprised by incident

5Almost

certain

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

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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 likelihoodscore for an individual risk

III. Risk Categorized and Semi-Quantified

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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.

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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.

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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.

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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.

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IV. Causes and Effects & Tools for Better Investigation

Process repeats to create a

causation system (cause-

and-effect continuum)

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Force Field AnalysisOnce 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 solely-

Benzalkonium-Chloride-preserved product and (ii) sterile filter all batching H2O.

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 root-

cause-analyses and force-field analysis—see below):

DRIVING FORCES 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

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IV. Causes and Effects & Tools for Better InvestigationThe Fishbone isn’t an ―End All‖—Just one Brainstorm Aide!

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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

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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.

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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;

•Must have the ability to take corrective action

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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

IV. Causes and Effects & Tools for Better Investigation

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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 non-conformity 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

V. Corrective Action Completeness and Effectiveness

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―Walter Shewhart conceptualized the ―Plan, Do,

Check, Act‖ cycle.

However, many practice only the second step, which

results in a ―Do Do‖ organization‖ –Anonymous

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

V. Corrective Action Completeness and Effectiveness

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―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.

V. Corrective Action Completeness and Effectiveness

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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.

Note: Corrective Action completeness ≠ effectiveness!

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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.

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VI. GMP/Quality Maturity Models and Relevant QuotesQuality Management Maturity Grid of Philip Crosby

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Spectrum of GMP & Quality Believers/Learners(Like GE Jack Welch‘s 10% non-achieving, 70% highly achieving, & 20% super-achieving)

A Zealot Devoted to

Quality, a Role Model,

a Trainer, a SageEasily

Trainable,

Positively

Impressionable

Initially

Skeptical,

then

Progressively

Trainable

Incorrigible,

Non-Believing,

Untrainable

VI. GMP/Quality Maturity Models

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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

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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.

VII. GMP/Quality Maturity Models

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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.

VII. GMP/Quality Maturity Models

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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 in-process 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.

VII. GMP/Quality Maturity Models

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―Even if you’re on the right

track, you’ll get run over if you

just sit there.‖—Will Rogers

VII. GMP/Quality Maturity Models

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