cv for a combination product - · pdf fileiq proper installation oq ... oq basic...

VALIDATING CLEANING PROCESSES FOR EQUIPMENT USED TO

MANUFACTURE A COMBINATION PRODUCT

A Case Study with a few “War Stories”

Christine Kielhorn, Ph.D. and Rich Yeaton

Atlantic Technical and Validation Services

1Copyright 2016 by

Atlantic Technical and Validation Services

AGENDA

• Discuss Combination Products in general

• Review the Product and Its Manufacturing Process

• Validation Project Planning

• Risk Management Approach to Cleaning Validation

• Implementing a Cleaning Validation Master Plan (CVMP)

– Lessons learned

• Discuss particulates as a soil

2

COMBINATION PRODUCTS

• A Medical Device with an Active Pharmaceutical Ingredient (API)

– Example: antibiotic coated stents

• A Medical Device that’s produced biologically

– Example: human skin grafts grown up from seed skin cells

• Drug Product packaged in a Medical Device

– Example: Epi pen autoinjector

• Drug Product sold with a Medical Device

– Example: Photosensitive drug product sold with an activating light source 3


WHICH REGULATIONS APPLY?

• They all can:

– 210

– 211

– 600 (if biologic in nature)

– 820

• The Code of Federal Regulations (CFR) are LAWS and must be followed or government intervention will occur

4


GENERAL OBSERVATION

• Medical Device manufacturers are extremely apprehensive of Parts 210 and 211

• Drug manufacturers are extremely apprehensive of Parts 820

• This is normal

• Personal observation: Parts 210, 211 and 820 have more in common than most people think

5

FDA OFFICE OF COMBINATION PRODUCTS

(OCP)

• They determine the Primary Mode of Action (PMOA) of the Combination Product

• This determines which group will lead the Investigation effort:

– Center for Biological Evaluation and Research (CBER)

– Center for Drug Evaluation and Research (CDER)

– Center for Device and Radiological Health (CDRH)

6

OCP (CONTINUED)

• They understand that most Combination Product manufacturers will be new to some parts of the Regulations

• Recommendation: be up front with the Agency

– Tell them you want to learn from the process

– Don’t try to hide problems

• The Agency knows you had some

• This goes against Conventional Wisdom

– A “war story” with a resolution can give you credibility

7

Observations Regarding the FDA

• Patient safety is their number 1 concern

– Which means that they can be persuaded with good rationales and data

– This can take a lot of work, so pick your battles and have lots of data

8

More Observations Regarding the FDA

• They’re not the bad guys

• They’re professional skeptics

– All claims must be backed up with data

– You’re allowed to disagree with them

• They may play mind games with you

• I haven’t met the “Inspector from Hell” yet

9

More Observations Regarding the FDA

• Bottom line: You need to convince them that you know what you’re doing:

– You understand your manufacturing processes

– You understand your Quality System

– You know how they work together

– You demonstrate process and Quality System periodic review and improvements (Quality Management Reviews, CAPAs, Continuous Improvement projects)

10

A “War Story” Regarding the OCP

• A long term client had a Commercial license to produce skin patches grown up from human skin cells

• These patches were regarded as Medical Devices for several years

• A few years ago, when the client notified the FDA of a process improvement, the decided that the improved patches were actually a Combination Product

– The client had to go through the Pre Approval Inspection process again

11

Key Learning regarding the OCP

• THEY decide whether a product is a Combination Product

12

Case Study – A Device/Biologic Combination Product

• Note: the following product and process descriptions have been thoroughly “sanitized” for Confidentiality reasons

13


• The product is a flexible organic Dura membrane patch

• It acts like a patch on a bicycle inner tube to minimize cerebrospinal fluid leakage after brain surgery

– Part of the Blood/Brain barrier

• This patch is a Medical Device version of an excipient

– No pharmaceutical or nutritive effects

• The organic patch material is grown up biologically

14


• Upstream process is a fairly standard microbial fermentation train

– Stagnant fermentation

– The desired organic material forms on the media surface

• Theory is that this material provides shade to the organisms

– Final fermentation step takes place in square trays held in HEPA filtered incubators

• Product looks like a dirty paper towel floating on top of the media

15


• Downstream Purification process is a series of heated and agitated caustic soaks followed by pressing fluid out of the material

– Organisms are gram negative, so the Purification goal is to depyrogenate the product

– We were essentially cleaning a sponge

• Soak, squeeze, repeat

• Patch material could hold a significant amount of fluid

• This Purification process was performed in jacketed stainless steel vessels

16


• Product depyrogenation was documented in a series of Development Studies

– Included in the product’s Device Master File (DMF)

• The cleaning of the Purification vessels, presses and fermentation equipment was validated consistent with the FDA’s 2011 Process Validation (PV) Guidance document

17

IMDRF/GHTF PV v/s

2011 PV Oversimplified

18

GHTF PV 2011 PV

IQProper installation and

basic functionalityIQ Proper installation

OQShort term process

capability and rangingOQ Basic functionality

PQLong term process

stabilityPQ

Performance for max/min configurations

PVTrained personnel,

approved procedures, qualified equipment

PVTrained personnel,

approved procedures, qualified equipment

Combination Product PV Approach

• The client used the IMDRF/GHTF approach to validate the patch production process

– We took liberties with this where we thought it was appropriate and had data to support our decisions

• We used the 2011 PV approach to validate the equipment cleaning

– More appropriate to use for a “wet” process

– Cleaning Validation is a form of Process Validation

19

Combination Product PV ApproachPersonal Observation

• The FDA is generally skeptical of “cookie cutter” approaches to Process Validation

• Adapt your PV Approach to the specifics of your process where it makes sense

• Have supporting data wherever feasible

20

A “Decent” rationale with a small amount of supporting data >> A great rationale without

supporting data

Guidances and Regulations

Guidances Regulations

21

Applicable Guidance Documents

• IMDRF/GHTF PV Guidance

• FDA 2011 PV Guidance

• FDA 1993 Guide to Inspections Validation of Cleaning Processes

– This states that for product dedicated equipment, “the firm need only meet a criteria of ‘visibly clean’ ”.

22

Implementing the Equipment Cleaning Validation Effort

• We developed a Cleaning Validation Master Plan (CVMP)

– This is a Controlled document

• Avoided the “Validation By The Pound” trap

• Approved CVMP was 27 pages in length

– 10 pages of content– 2 pages for Approval page and TOC– 15 pages of Exhibits

23

The CVMP and the KISS principle

• KISS: Keep it Simple, Stupid

• We believe that a CVMP is a “strategic” document and should be kept to less than 20 pages in length

– It’s hard to “wrap your mind” around larger documents

– (FDA Investigators) “Don’t have a lot of time or a lot of patience” (Client quote after a PAI)

24

The CVMP and the KISS principle

• Experience has taught us that the “Executive Summary works VERY well:

– A concise Narrative section

– Followed by multiple Exhibits that provide supporting detail

• If an Investigator wants to see an Exhibit for the supporting detail, it’s right there

25

CVMP Table of Contents

• Scope

• References

• Process Description

• Risk Assessments

• Cleaning Critical Quality Attributes (CQAs) and Verification Methods

• Potential Cleaning Critical Process Parameters (CPPs)

• Acceptance Criteria Determination

• CV Development Studies

• Ongoing Monitoring Determination

26

CVMP Exhibits

• Process Flow Diagrams (PFDs)

• Lists of Equipment and Parts to be cleaned

• Risk Assessments:

– Soils

– Equipment locations to be sampled for cleanliness

– Cleaning Challenge of Parts to be cleaned in the Parts Washer

• Lists of potential Cleaning CPPs27

Risk Assessments

• Used to assess soils, sampling locations and parts to be sampled for cleanliness

• We recommend a Failure Mode Effects Analysis

– Simple

– Easy to automate in Excel

– Color code to identify High, Medium and Low Risk items

• “Traffic Light” coloring

28

Soil Risk Assessments

• RM = PF x PS x PD

• RM could range from 1 to 27

29

Failure Mode Description

PFProbability that the soil would not be adequately removed/reduced

PSAssessed severity of the failure mode (Risk to Patient Safety) if it occurred

PDAssessed likelihood that the failure mode could occur without being detected

Soil Risk Assessment

Failure Mode PF PS PD RM Potential SISPQ Impact

Insufficient endotoxin reduction

3 3 3 27Endotoxins are produced by the production organism used to manufacture the patch; endotoxin is not visibly apparent

Residual patch fragment carryover

3 3 3 27Particles could cause blockages in patient blood vessels

Insufficient residual media

reduction2 3 2 12

Residual media could support microbial growth after production and terminal sterilization

Insufficient caustic

reduction2 3 1 6 Residual caustic can be toxic

Insufficient cleaning agent

reduction2 3 1 6

Residual caustic +/or acidic agents will be detected by rinsewater conductivity

Insufficient bioburden reduction

1 3 1 3Although the product is sterilized after packaging, sterilized bioburden can result in pyrogen contamination 30

Risk Assessment Scoring Recommendation

• Calculating the product of these scores made it pretty easy to identify High Risk items

• You can use a finer resolution for scoring, but beware of nitpickers

31

Risk Score

High 3

Moderate 2

Low 1

Part Cleaned in the Parts Washer Risk Assessment

• CCP = PPC x Pg x Ps

32

Failure Mode Description

PPC

Degree of contact with Final Product:3: contact with patch2: contact with fermentation broth1: no contact with broth or patch

PG Geometric complexity of part

Ps Part size

Cleaning Processes to be Validated

Equipment Cleaning Process

Purification Tanks Automated Clean In Place (CIP)

Presses Manual

Fermentation Components Clean Out of Place (COP) in automated Parts Washer

33

Manual Cleaning

34

• Challenge is to minimize human variability

• Cleaning procedures must be painfully specific

– Specify minimum number of horizontal/vertical strokes

– Specify minimum rinse volumes

• Document personnel training on these procedures

• Recommend single use cleaning implements

CIP system design

35

XV111

PT115

2"1-1/2"

PU-302

TI107

1

2

PI115

SightGlass LGH

L-1

SB114

SG113

Dip tube

HV111A

HV111B

2"1-1/2"

2"

PU-301

1-1/2"2"1-1/2"

Waste

HV111CXV

116CV111

LT108

HV104

FI201

AV102

LI108

WSP

Vent

1

HV103A

FI202

2PU-302 VFD Connection

XV115

CV103

SC115

FL05

FL05

FL08

FL09

FLyy

FLzz

FLxx

Arkay Cabinet

Condensate collection

33FL

10

Comp Air

Semiautomated CIP system Cycle

36

• Initial potable water rinse

• Caustic wash

– Cleaning CPPs:• Temperature

• Recirculation time

• Recirculation flowrate (to maintain turbulent flow)

• Acid wash

– Same CPPs

• Triplicate Purified Water rinses

• Compressed Air drying

Equipment Dirty Hold Times

37

• The longer you allow soiled equipment to sit idle, the harder it will be to clean

• The Agency will expect you to have data to support your Dirty Hold Time (DHT) claims

• This means that you’ll have to soil your equipment, allow it to sit idle for some period of time, clean it and prove that it’s clean

Equipment Dirty Hold TimesImplications

38

• Operations will have conflicting desires

– Long DHT v/s scheduling flexibility

• The Agency will expect you to state your DHT in a procedure

– State what to do if the DHT is exceeded

– You’ll need data to support this situation as well

Equipment Dirty Hold TimesImplications

39

• Whatever DHT you demonstrate, you’ll need a Safety Factor

– If you have data to support a 4 day DHT, you should state a 3 day DHT in your procedure

– This is not a Regulatory requirement, but pick your battles

Combination Product Case Study Equipment DHT

40

• Purification tanks and presses:

– We claimed a 1 hour DHT in the CVMP and the Cleaning Procedures

– We tested a 2 hour DHT during Cleaning Validation

– Operations decided that would rather pay two hours of Overtime occasionally rather than allow their equipment to sit idle overnight

– We also proceduralized a potable water flush at the end of each production cycle

Combination Product Case Study Equipment DHT

41

• Parts cleaned in the Parts Washer:

– Soiled parts were stored in the Parts Washer overnight for a minimum of 16 hours

– The cleaning of these parts was validated• 12 hour DHT claimed

– As an additional Cleaning Challenge, these parts were not rinsed during Cleaning Validation prior to being placed in the Parts Washer• Purified water rinse is required for these parts in the Parts Washer

procedure

Clean Hold Time (CHT)

42

• The Agency will expect you to have data to support how long you can claim to hold clean equipment idle before recleaning (prior to use in production) may be required

• In reality, CHTs will probably be much longer than what your data will support because Operations doesn’t like their equipment sitting idle

Combination Product Case Study Equipment CHT

43

• We measured surface TOC and bioburden during CHT testing

– Caused by growth in chance residual water or condensation

• We stated this in the CVMP

• We verified a 3 day CHT and claimed 2 days

– This allowed weekends

– Operations decided that an occasional 2 hour Cleaning cycle after a three day weekend was easier to manage than allowing the equipment to sit idle for 4 days

Using a Risk Management Approach to develop the CVMP

44

• First principle to developing a CVMP:

START OUT SIMPLE

Using a Risk Management Approach to develop the CVMP

45

• Documented Risk Assessments show that you’ve thought things through

– Even if an Investigator disagrees with a specific RPN

– It’s not uncommon for an Investigator to question an assessment that he/she agrees with

Risk Assessment Lesson Learned

46

• Graph the Risk Assessment

– Look for a “knee” in the curve

– It’s usually (but not always) there

Risk Assessment “Knee”

47

0

5

10

15

20

25

30

Endo Particles Media Caustic CleaningAgent

Bioburden

RP

N

Dura Patch Production ProcessInitial Soil Risk Assessment

Risk Assessment Lesson Learned

48

• Avoid spending effort on verifying things that your Risk Assessment says are low priority

– There’s a tendency among some QA people to do this “just to be safe”

– Implies that you don’t believe your own Assessment

The CVMP can serve multiple purposes

49

• It gives you a plan to follow

– It’s surprising how many competent operating companies skip or minimize this step

“The best thing about not planning is that failure comes as a complete surprise”

James Agallaco

The CVMP can serve multiple purposes

50

• A post-execution review of the CVMP will show how the project actually happened

• A recap of Process Development efforts is an FDA expectation according to the 2011 PV Guidance

– This will give you a chance to learn form experience

– Again, it’s surprising how rare this is

The Process Design section of the 2011 PV Guidance

• The FDA talks about two subsections to Process Design:

– Building and Capturing Process Knowledge and Understanding

– Establishing a Strategy for Process Control

51

Building and Capturing Process Knowledge

• This is where you describe your Cleaning Validation Process Development efforts

• The Guidance states that these experiments generally do not need to be performed under cGMP conditions

– Lots of smaller scale lab work here

52


• Cleaning PD experiments should be scientifically sound

• PD data should be recorded consistent with Good Documentation Practices

– Train your PD people on GDPs

– Expect some resistance

• The Guidance states that PD efforts should be consistent with Q10

53


• The Agency expects that you’ll learn things during PD

• You may define new CQAs/CPPs as part of this effort

– Or de-emphasize one or more

• “FDA does not generally expect manufacturers to develop and test the process until it fails.”

54

Combination ProductCleaning PD Efforts

• Swab Recovery Factor (SRF) Studies

– TOC

– Endotoxin

• Cleaning Cycle Development Studies

55

SRF Studies

• Obtain 10 coupons of each of the materials you want to study

– 316L Stainless Steel

• Preclean these coupons

– NaOH soak

– USP PW rinse

– Air dry

56

SRF Studies

57

1:1 1:1 1:1

2:1 2:1 2:1

4:1 4:1 4:1

NC

SRF Studies

• Allow dispensed media to air dry in a BSC

– We labelled paper towels with the concentration and placed the coupons on the towels

• Swab the coupons per an approved Swabbing SOP

𝑺𝑹𝑭 =𝑹𝒆𝒑𝒐𝒓𝒕𝒆𝒅 𝑻𝑶𝑪 𝒍𝒆𝒗𝒆𝒍

𝑷𝑪 𝑻𝑶𝑪 𝒍𝒆𝒗𝒆𝒍

58

SRF Studies: Lessons Learned

• TOC is a “broadband” detection method and will detect any kind of TOC

– “Finger schmutz”

– Be careful when you spray IPA near the coupons

– We make a practice of disregarding any SRF values greater than 100%

• We also recommend using the lowest calculated SRF value to calculate actual TOC levels during Cleaning Validation

59

SRF Studies – Lessons Learned

• Endotoxin cannot be reliably recovered from most surfaces by swabbing

• There is published data confirming this

– Bacterial Endotoxin Testing: A Report on the Methods, Background, Data and Regulatory History of Extraction Recovery Efficiency

– Dr. Victoria Hitchens (OST, US FDA) is a contributing author

60

SRF Studies – Lessons Learned

• We included a rationale in the Endo SRF report stating that the only mechanism we could identify for endotoxin to transfer from the tank surface to the product was via the wash/rinse water in the tank.

• We therefore sampled the rinsewater for endotoxin during CD and Cleaning Validation

61

Cleaning Cycle Development Study

• We identified Cleaning CPPs based on the following rationales:

62

CPP Rationale

Fill volume Above production “ring”

Cleaning solution temperature Production setpoint (60° C)

Recirculation flowrate Above turbulent flow

Recirculation time Sufficient to achieve 10 volume changes

Cleaning agent concentration 1 N (Production concentration)

Acid Cleaning Agent Use

• We weren’t sure if we needed this, but included it because it would neutralize residual caustic

• Manufacturer said that use of an acid cleaning agent would “augment” the passivated oxide layer on the stainless steel

63

Cleaning Cycle Development Study

• We ran a Cleaning Cycle using these CPPs

• We measured rinsewater endotoxin and particulate levels as they were the two most critical CQAs according to our Soil Risk Assessment

• We measured surface TOC for informational purposes

– FDA talks about the “dirty pot”

• We also measured rinsewater conductivity to confirm cleaning agent removal

64

Cleaning Cycle Development StudyCQAs

65

CQA Target

Visible residue Visually clean (no visible residue)

Rinsewater Endotoxin Meets WFI specifications

Rinsewater Particles Meets USP <788> specifications

Rinsewater Conductivity Meets WFI specifications

Surface TOC Report results

Rinsewater bioburden Meets USP PW specifications

Cleaning Cycle Development StudyResults

• We got it right the first time

• Which probably means we were overkilling things

66

Cleaning Validation Acceptance Criteria

CQA Acceptance Criteria

Visible residue Visually clean (no visible residue)

Rinsewater Endotoxin Meets WFI specifications

Rinsewater Particles Meets USP <788> specifications

Rinsewater Conductivity Meets WFI specifications

Surface TOC Less than 150% of CD results

Rinsewater bioburden Meets USP PW specifications

67

Risk Mitigation

68

• We recommend including an Assessment of any Risk Mitigation measures you implement in the CVMP

Risk Mitigation

69

Failure Mode Risk Mitigation Activity PF PS PD RM

Insufficient endotoxin reduction

Heated caustic wash step, triplicate PW rinses, endotoxin testing of rinsewater during Cleaning Validation

1 3 1 3

Residual patch fragment carryover

Rinsewater particle analysis of rinsewater during Cleaning Validation

1 3 1 3

Insufficient residual media

reduction

TOC sampling of product contact surfaces during Cleaning Validation

1 3 1 3

Insufficient caustic reduction

Conductivity testing of rinsewater during Cleaning Validation, ongoing monitoring of rinsewater conductivity during Operations

1 3 1 3

Insufficient cleaning agent

reduction

Conductivity testing of rinsewater during Cleaning Validation, ongoing monitoring of rinsewater conductivity during Operations

1 3 1 3

Insufficient bioburden reduction

Bioburden testing of rinsewater during Cleaning Validation

1 3 1 3

CVMP Review

• Don’t hesitate to review and revise the CVMP as you work the plan

• The FDA knows that Murphy’s Law is a real thing

– Don’t try telling them that everything went according to plan – they won’t believe you

“No battle plan survives contact with the Enemy”Attributed to General Robert E. Lee

70

CVMP Review

71

FDA and Particles

• The FDA is raising its expectations regarding visual inspection of injectable drugs

– Reference USP <1> and <790>

• Genzyme – visible particles in injectables

• The FDA will probably start to apply this to implantable devices

• Davol (Hernia repair implants) have procedures for measuring particles

72

Current Regulatory Environment

• EN 45502

• ISO 8536

• ANSI/AAMI AT6

• AAMI Technical Report TIR42

• USP <1>

• USP <788>

• USP <790>

73

Suggested Testing Protocol: Subvisible Particles

• EN 45502 is better starting point than USP <788>

• Solvent volume proportional to device surface area

74

Suggested Testing Protocol:Subvisible Particles

75

Know Your Process

•Understand sources of potential particulates

Identify Appropriate Particle Extraction Solvent

Develop Extraction Method

•Appropriate for device geometry

Set Limits

Suggested Testing Protocol: SubvisibleParticles

• Understand sources of potential particulates

76

Membrane Microscopy IR Spectroscopy

Know Your Process

Suggested Testing Protocol: Subvisible Particles

• Identify appropriate particle extraction solvent

77

Surface Chemistry of Device

Particle Free Water (PFW)

Saline Solution

Chemical Identity of Particulates

Alcohol solution


• Volume of particle extraction solvent = 5 times the device surface area

• Immerse device, extract particles and measure

– Light Obscuration is industry standard

78


• Method development:

– Immersion time

79

Incubate for 10 min.

Measure Particles

Incubate 10 min.

Measure Particles

Is particle count < 10-20% of Total?

NO

YES

Immersion Time Found


• Calculate particle contamination in terms of particles per device:

80

𝑃 = (𝑅 − 𝐵) × 𝐴 × 5

P – Total number of particles on DeviceR – Result in Particles/mL from Particle CounterB – Blank MeasurementA – Contact Surface Area

Visible Particles in Parenterals

• Covered in USP <1>

• Visual Inspection expectations are outlined in USP <790>

– 100% Visual Inspection during manufacturing is specified

– Followed by a Batch Release sample inspection

81

Visual Inspection Issues

• People aren’t perfect

– 80% accuracy is Industry Practice

– Operator fatigue is a real thing

– Not everyone can reliably Inspect

• Visual Inspection environment must be controlled

– Inspection booths

– Lighting and backgrounds

– Cleanrooms82

Visual Inspection Issues

• Inspectors should be Trained and Qualified

– This Qualification should be documented and maintained

– Annual Requalification is recommended

• Defect Library should be developed and maintained

– “Standard” defects are commercially available

83

Particle Sources

• Production process itself

– Patch cutting

– Vial filling

• Stopper fragments

• Glass shards

• Production environment

– Skin cells

– Hair fragments

– Gown fibers

84

Particle Prevention

• Engineering approach

– Include filters in water system

• Focus should be on eliminating potential sources of particle contamination rather than catching particles via visual inspection

• Demonstrate diligence

85

Suggested Testing Protocol: Visible Particles

• Treat like sterility: you want zero but can’t prove it

• Aseptic operations routinely performs media fills:

– Fill a minimum of 3000 vials with your aseptic process

– No growth demonstrates a 95% confidence level that the failure rate is less than 1 per 1000 vials

86

Suggested Testing Protocol: Visible Particles

Medical Devices Vials or Syringes

Rinse 3000 parts in 5X surface area Particle Free Water (PFW)

Fill 3000 vials with PFW

Collect rinsate Decant and collect filled liquid

Analyze collected water with automated Light Obscuration particle analyzer

No visible (>120 µm) particles detected interpreted as indicating a 95% confidence level that the defect (particle presence) rate is

less than 1/1000

87

What do YOU Think?

• Give us 3-5 good reasons (scientific or GMP) that the sterile fill approach won’t work for visible particle inspections.

88

Responses to Group Activity

• It hasn’t been done before

– FDA will accept a good rationale backed up by sound data

89


• Recovery studies will be required

90


• The FDA won’t accept the premise.

91


• A single product (vial, device, syringe) with visible particles will trigger a recall

92

Questions?

Feel free to contact either of us at:

[email protected]

[email protected]

93