Top Annual 483 Observations: The Cycle of Quality June ...

Top Annual 483 Observations: The Cycle of Quality

June 2017

Presented by: Susan Schniepp

2016 © Regulatory Compliance Associates Inc.

W E L L N E S S F O R B U S I N E S S ®

2

Top Observation for 5 years

Year Drugs #1 citation Device #1 citation Biologics #1 citation

2016 211.22(d) 820.100(a) 606.100(b)

2015 211.22(d) 820.100(a) 606.100(b)

2014 211.22(d) 820.100(a) 606.100(b)

2013 211.22(d) 820.100(a) 606.100(b)

2012 211.22(d) 820.100(a) 606.100(b)

21 CFR 211.22(d) states “The responsibilities and procedures applicable to the quality control unit shall be in writing. Such written procedures shall be followed.” 21 CFR 820.100(a) states “Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. 21 CFR 606.100(b) states “Establishments must establish, maintain, and follow written standard operating procedures…”


3

Other Observations 2016 2015 2014 2013

#2 Inadequate lab

controls

Inadequate lab

controls

Inadequate lab

controls

Investigations

#3 Investigations Investigations Investigations Absence of

written

procedures

#4 Absence of

written

procedures

No procedures

to prevent

microbial

contamination

Absence of

written

procedures

Inadequate lab

controls

#5 EM procedures

inadequate

Absence of

written

procedures

Written

procedure not

followed/establi

shed

Written

procedure not

followed/establis

hed


4

Discussion Topics

What’s Going on with SOPs?

What’s Going on with Investigations?



5

Definition of an SOP



6

Definition standard operating procedure, n.

1. Established procedure to be followed in carrying out a given operation or in a given situation.

2. A specific procedure or set of procedures so established. – American Heritage® Dictionary of the English Language, Fifth Edition.

3. A set of fixed instructions or steps for carrying out routine operations. Abbr.: SOP

– Random House Kernerman Webster's College Dictionary, © 2010

4. A set of instructions covering those features of operations which lend themselves to a definite or standardized procedure without loss of effectiveness. The procedure is applicable unless ordered otherwise. Also called SOP.

– Dictionary of Military and Associated Terms. US Department of Defense 2005.


http://www.thefreedictionary.com/sop

http://www.thefreedictionary.com/sop


7

Why do we write SOPs



8

Why Do We Write SOPs?

Because:

•Personnel can conduct operations with

Consistency

•Assures Quality Consistency

•Assures Regulatory Compliance

•Makes Good Business Sense



9

Do NOT Write SOPs

For Regulators, OR

Because you think they are required

by the regulations

SOPs written for these reasons are not based on your

operations and often lead to compliance troubles.



10

SOP Characteristics



11

Characteristics of a Good SOP • Tailored to your organizational design and needs.

–Provides sufficient detail to allow your personnel to conduct

operations as management wants. If you have a very

experienced work force you may need less detail.

–Takes into account who has the authority to make decisions.

–Clearly defines accountability (i.e. who performs what

actions).

–Provides guidance on what to do when things don’t go right.

–Defines decision points and actions to take for each decision.



12

Characteristics of a Good SOP(Cont.)

• Defines/Specifies

–Outputs From Each Process (documentation, work product, etc.)

–Process Owners

•Assures process is working

•Can initiate change

–Process Stakeholders

•Run the process

–Trainees



13

How Do We Get There?



14

How Do We Accomplish This?

• SOPs should have:

–Clear Instructions

–Instructions may be in one or various styles

• Playscript (operator does “a” now and “b” next)

• General description – paragraph form

• Flow chart

• Pictorial

• OR ANY COMBINATION as long as personnel can follow



15

How Do We Accomplish This? (Cont.)

• Type of style and level of detail depends on what would be

most effective for your personnel

–Experienced vs. Inexperienced Employee

–Predominate primary language may not be English

–May Need Dual Language SOPs



16

Essential SOP Elements



17

Seven Basic Format Requirements

1. Unique Identifying Number & Title

2. Effective Date

3. Purpose and Scope

4. Roles and Responsibilities

5. Change History

6. Official Signatures

7. Step-by-Step Instructions



18

1. Unique Identifier = Unique Title

• Document Identifier:

–Assigned by Document Control

–Is often combination of Alpha/Numeric Characters

• Unique Title:

–Assigned by Applicable Area

–Should Reflect the Operation

–Should be Specific Enough to Avoid Confusion



19

Examples

•QC-001.01 QC Laboratory OOS Procedure

– QC is Department Owner

– 001 is the Document Sequence Number

– .01 is the Revision Number

– QC Laboratory OOS Procedure is the Title



20

2. Effective Date

• The Date the Document Instructions are Official

–Assigned after completion of training

–Assigned after official signatures are obtained

–Represents the most current version of SOP

–Should be traceable to Unique Identifier and Title



21

Examples

• Some Date Formats

–08-30-15

–08/30/15

–30 Aug 15

–30 Aug 2015

• Dates Should be Legible and Readable

• Format of Date is Not Important



22

3. Purpose and Scope

• Purpose

–Describes the Reason for the SOP

• Scope

–Describes the boundaries of the SOP



23

Examples

• Purpose: The purpose of this SOP is to describe the

procedure for establishing raw material

specifications.

• Scope: This procedures applies to components and

materials used in the manufacturing of drug

products.



24

4. Roles and Responsibilities

• Defines Who Can Initiate Changes to SOP Content

• Defines Who does What at a High Level

• Defines Who should be Trained



25

Examples

• Quality Control is responsible for testing the

components and materials.

• Quality Assurance is responsible for reviewing and

approving the results of the QC tests.



26

5. Change History

• Describes what has changed between versions

• Describes the Reasons for Changing the SOP



27

Examples

• Reason for Change: This SOP was established to

define the process for review and approval of QC

laboratory test results.

• Reason for Change: Step 5 of the SOP was changed

to clarify that Quality Assurance has the final

approval of QC test results.



28

6. Official Signatures

• Management Acknowledgement

–Changes are consistent with policy/procedure

–Changes are necessary

–Changes do not impact

• Quality of Product

• Validation Status of Product



29

7. Step-by-Step Instructions

• Defines the steps in the operation being performed from

initiation to completion of the task

–Written Language should be Clear and Concise

–Consider flow diagrams

–Consider pictures

–Consider Combinations

–Detail Depends on Company Philosophy

–Should be ≤ 10 pages

–If ≥10 pages consider smaller sections



30

Additional Considerations • Reference to Related SOPs

– Useful in identifying documents also requiring revision

• References to Regulatory Requirements

– Helps identify the origin of the requirement

– May help identify documents needing changes based on regulation changes

• Attachments

– Helps ensure changes in the SOP are carried through to related documents

• Definitions

– Defines terms specific to the SOP

• Deviation / Failure Response (What to do/Where to go/Who to involve)

– Identify steps necessary to involve QA and initiate a formal investigation (OOT, OOS, Deviation, CAPA, etc…)



31

Avoiding Pitfalls



32

Common SOP Pitfalls 1. Providing too much information

– Requirement: Use a Pentel® R.S.V.P.® Ballpoint Stick Pen with Grip; Fine

Point, Black Part #BK90-A

• Why is this a pitfall: Using a different pen is a deviation from your SOP

2. Providing too little information

– No requirement specified regarding the use of writing tool.

• Why is this a pitfall: It allows for the use of any writing implement including

Pencil.

• Acceptable Statement: “Using a blue or black indelible pen…”



33

Other Pitfalls 3. Using the manufacturer’s supplied SOP verbatim

“if equipped with optional ABC-123 printer…”

– You either have the printer or not

4. Leaving things for individual interpretation causing lack of consistency

between operators

– Pitfall: “Inspect a sufficient number of units”

– Acceptable: “For a batch size between 101-500 units, inspect 12 units”

5. Not having SOP available in the area at the time of use

– Can’t follow it from memory if it is a detailed stepwise instruction

– Operators will do what they were shown to do and not what their procedure

instructs them to do



34

Other Pitfalls (con’t)

• Allowing access to SOPs that are ‘out of date’

– “We removed that equipment 2 years ago…”

– Common to find tables from previous SOP version in Lab Notebooks

still being used

• Why is this a pitfall?

– People may not be performing the appropriate steps

– The information being generated may not be correct

– It calls into question your quality system and your document control

processes.



35

Summary • Don’t Write for Regulators - Write for Your Processes

• SOPs should be clear and concise and understood by the

intended user

• There is a fine line between being too specific vs. being too

general.

–Know your company’s philosophy on the level of detail to

be included.



36



37

Investigations



38

Regulations

• Required by law

–Food, Drug and Cosmetic Act

–21 CFR 211

–21 CFR 820

–EudraLex

–ISO

–ICH

–GHTF



39

Food, Drug and Cosmetic Act

• SEC. 501. [21 USC §351] (a)(2)(B)

– a drug shall be deemed to be adulterated if the methods used in, or the facilities or

controls used for, its manufacture, processing, packing, or holding do not conform

to or are not operated or administered in conformity with current good

manufacturing practice to assure that such drug meets the requirements of this Act as

to safety and has the identity and strength, and meets the quality and purity

characteristics, which it purports or is represented to possess.



40

21 CFR 211.22 (a) There shall be a quality control unit that shall have the responsibility and authority to

approve or reject all components, drug product containers, closures, in-process materials,

packaging material, labeling, and drug products, and the authority to review production

records to assure that no errors have occurred or, if errors have occurred, that they have

been fully investigated. The quality control unit shall be responsible for approving or

rejecting drug products manufactured, processed, packed, or held under contract by

another company.



41

21 CFR 820 820.100: “Investigating the cause of nonconformities relating to product,

processes, and the quality system”

820.198: “Any complaint involving the possible failure of a device, labeling,

or packaging to meet any of its specifications shall be reviewed, evaluated, and

investigated.”

820.90: “The evaluation and any investigation shall be documented.”

820.100: “Corrective and preventive action. (a)Each manufacturer shall

establish and maintain procedures for implementing corrective and

preventive action”



42

EudraLex Volume 4

• A Pharmaceutical Quality System appropriate for the manufacture of medicinal

products should ensure that:

– The results of product and processes monitoring are taken into account in batch

release, in the investigation of deviations, and, with a view to taking preventive

action to avoid potential deviations occurring in the future.

– An appropriate level of root cause analysis should be applied during the

investigation of deviations, suspected product defects and other problems.

– Appropriate corrective actions and/or preventative actions (CAPAs) should be

identified and taken in response to investigations.

– A review of all batches that failed to meet established specification(s) and their

investigation.

– A review of all quality-related returns, complaints and recalls and the

investigations performed at the time.



43

Other

• International Organization for Standardization (ISO)

– ISO 13485: Quality Management for Medical Devices

• International Conference on Harmonization (ICH)

– Q10: Pharmaceutical Quality System

• Global Harmonization Task Force* (GHTF)

–Quality management system –Medical Devices – Guidance on

corrective action and preventive action and related QMS processes

*The International Medical Device Regulators Forum (IMDRF) is continuing the work of the Global Harmonization Task

Force (GHTF).



44

What is CAPA?



45

The CAPA Process



46

Key Point to Remember

CAPA System

Identifying Issues

Production and Process

nonconformances

Complaints

Audit Observations

Trends

Investigating to root

cause

Resolving the

Issues Verifying the

Resolution Corrections

Interim Controls

Corrective Action

Preventive Action

Effectiveness

Checks

Performing Risk

Assessment



47

Risk Assessment

• What is the impact of the issue to the health and safety of the

patient and/or user.

• What is the scope of the issue:

• Product in the field

• Multiple lots

• Multiple locations

• Frequency of occurrence

• Identified in Hazard Analysis

• Use your Risk Management Tools.



48

Investigations

If an initial evaluation and risk assessment indicates, a documented investigation consistent with the significance of the quality issue, is performed to determine Root or Probable Cause.



49

Investigations continued

• Initial Risk Assessment will determine the:

• Depth of investigation:

• Simple issues = simple investigations

• Complex/safety critical issues = detailed

investigations

• Urgency of the investigation.

• Obtain Quality Management support


50


• Write an Investigation Plan.

• Identify an Owner (process or event).

• Engage a team if applicable.

• Determine tools to be used.

• Determine areas to be investigated.

• Determine how to investigate.

• Establish a timeline.



51


• Investigate the following areas:

–Personnel,

–Materials,

–Equipment,

–Process/Methods,

–Suppliers,

–Validation,

–Storage conditions,

•Think big, think creatively.



52


Document all investigation activities.

• At a minimum, include the following elements:

–Description of Nonconformity Event

–Root or Probable Cause

–Outcomes of all tools used

–Objective evidence supporting conclusions

–Description of statistical methods used

–Final risk assessment



53

Investigative Tools •Brainstorming

•Fishbone

•5 Whys

•Design of Experiments

•Contradiction Analysis


www.rcainc.com, News and Views, News

http://www.rcainc.com/


54

Correction

• Correction: Action taken to fix a

detected nonconformity.

–Typically one time fixes.

– Immediate solution such as training, repair or rework.

– Also known as remedial or containment action.

• Corrections require verification.

• Thorough documentation required



55

Correction, continued

• Interim controls

–Type of correction that remains in place until a corrective

action is deemed effective

• Examples

–100% inspection

–Third party oversight and review


56

Corrective Action

• Corrective action (CA): action to eliminate the

cause(s) of a detected nonconformity or other

undesirable situation and the recurrence of the issue.



57

Corrective Action continued

•Write a Corrective Action Plan.

–Identify the CA strategy.

–Describe all the corrective actions that will be

performed and associated action items.

–How will the corrective action be tested

–Identify who is responsible for each

action item.

–Set a timeline with completion dates.



58

Corrective Action continued

• Implement the Corrective Action(s).

• Implementation requires monitoring and oversight.

–Structured monitoring of progress against actions, monitoring

of the impact of actions, engagement of management, and

governance.

–Documents any changes, and reflects any revisions or changes

to timelines in the documentation.

–Formal tracking of the overall progress of the CA, tracking of

the individual actions, and review of milestones on a defined

frequency.



59

Preventive Action • Preventive Action (PA): action to eliminate the cause of a

potential nonconformity or other undesirable potential

situation. Should prevent the occurrence of the potential issue.

• Not dependent on the occurrence of a

nonconformity

• Example: Results of a Finished

Product QC check are within

specification limits yet over the past 10 batches are trending

upward.



60

Preventive Action continued

•Preventive action require a plan with same

elements as a corrective action:

•Write a plan.

•Implement the preventive actions.

•Monitor preventive action activities.



61

Effectiveness Check

Effectiveness Check (EC): Monitoring activity over

a defined duration for ensuring that

• CA/PA’s have been identified, implemented, and

sustained

• the problem has been solved, and

• no new quality problems

have been created.



62

Effectiveness Check continued • Key Components of Effectiveness Checks:

–Methods for determining success of the Corrective Action

or Preventive Action must be defined.

–Effectiveness criteria or key performance indicators must be

measurable.

–Duration for conducting effectiveness checks must

determined.

–Data, graphs, charts, metrics as applicable

for evidence of effectiveness of the

Corrective or Preventive Action



63

Effectiveness Check continued

Effectiveness Check Plan:

• Addresses the key elements.

• Describes statistical techniques to be used.

• Lists responsibilities and includes due dates.



64

CAPA Closure

•All actions must be completed and

assessed for effectiveness prior to CAPA

closure. (Note: In rare occasions CAPA may be closed prior to effectiveness

check however solid justification is required.)

•Use common sense



65

Corrective Action/Preventive Action

–Not all nonconformities require Corrective or

Preventive Action.

–If Corrective or Preventive Action are not

necessary, as determined by Quality, then

appropriate justifications should be

documented and approved.



66

Corrective Action/Preventive Action continued

•Low Level Investigations may not routinely require CAPAs.

•However, these investigations should be tracked and trended.

• If a recurring trend is found, Corrective Actions should be required.



67

Corrective Action/Preventive Action continued

CAPA Leader

• Excellent communication/presentation skills.

• Strong analytical problem solving skills.

• Influence management skills; ability to work constructively

across all functions of the organization.

• Experience in all areas of the CAPA process.

• Experience with quality tools and process improvement

techniques.

• Project management experience.



68

When to Create a CAPA

• Not all nonconformance needs to become a CAPA.

• Use a method to determine if a CAPA is needed.

• Use a combination impact and frequency.



69



70


71

Top Annual 483 Observations: The Cycle of Quality June ...

Documents

Transcript of Top Annual 483 Observations: The Cycle of Quality June ...