Schedule - astm.org · E55 Manufacture of Pharmaceutical Products Hovione - Lisboa, Portugal Schedule E55 Manufacture of Pharmaceutical Products Meeting Hovione Farmaciencia Sa -

E55 Manufacture of Pharmaceutical Products Hovione - Lisboa, Portugal

Schedule

E55 Manufacture of Pharmaceutical Products Meeting

Hovione Farmaciencia Sa - 28-30 April 2015

Tuesday Hovione Farmaciencia Sa

8:30 - 5:00 PM Tours and Outreach

Wednesday Hovione Farmaciencia Sa

8:30 - 9:15 AM E55 Welcome and Opening

9:15 - 10:00 PM E55.04 Inactivation of Enveloped Viruses (WK39883)

10:00 - 10:15 AM Break

10:15 - 11:00 AM E55.04 Remove Virus by Filtration (Multiple WKs)

11:00 - 12:00 PM E55.04 Biocompatibility in SUS (WK48956 & WK48957)

12:00 - 1:00 PM Lunch

1:00 - 2:45 PM E55.04 Extractables Used in SUS (WK43975)

2:45 - 3:00 PM Break

3:00 - 3:45 PM E55.04 Integrity of single-use systems (WK43741 & WK47355)

3:45 - 5:00 PM E55.04 Characterization of SUS particulates (WK43742 & WK47356)

5:00 - 5:30 PM E55.04 General Biopharmaceutical Subcommittee

6:30 - 9:00 PM E55 Group Dinner (off-site)

*** E55.04 items will run consecutively.

Thursday Hovione Farmaciencia Sa

8:30 - 9:15 AM E55.01 Continuous Processing Revisions (E2968)

9:15 - 9:45 AM E55.01 Sampling (WK41265)

9:45 - 10:15 AM E55.01 PAT Mgmt/Implementation Subcommittee

10:15- 10:30 AM Break

10:30 - 11:30 PM

E55.03 Design & Verification of Single Use Pharma & Biopharma

(WK46541)

11:30 - 12:00 PM E55.03 Particle analysis Applications (WK30195)

12:00 - 1:00 PM Lunch

1:00 - 1:45 PM E55.03 Bacterial Retention / Filters (F838)

1:45 - 2:30 PM E55.03 General Pharmaceutical Subcommittee

2:30 - 2:45 AM Break

2:45 - 3:45 PM E55.91 Terminology Subcommittee

3:45 - 4:30 PM Roadmapping: Outreach and Education (E55.94)

4:30 - 5:00 PM E55 Main Closing


Standards

E55.01 Process Understanding and PAT System Management, Implementation and Practice

1. E2474-14 Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology

2. E2891-13 Guide for Multivariate Data Analysis in Pharmaceutical Development and Manufacturing Applications

3. E2898-14 Guide for Risk-Based Validation of Analytical Methods for PAT Applications 4. E2968-14 Guide for Application of Continuous Processing in the Pharmaceutical

Industry 5. E2475-10 Guide for Process Understanding Related to Pharmaceutical Manufacture

and Control / Status: Ballot Action Required 6. E2476-09 Guide for Risk Assessment and Risk Control as it Impacts the Design,

Development, and Operation of PAT Processes for Pharmaceutical Manufacture Status: Overdue

7. E2629-11 Guide for Verification of Process Analytical Technology (PAT) Enabled Control Systems

8. WK41265 Practice for Sampling (DRAFT) -(Technical Contact: Louis Traglia E55.03 General Pharmaceutical Standards

1. E2500-13 Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment

2. E2503-13 Practice for Qualification of Basket and Paddle Dissolution Apparatus 3. E2537-08 Guide for Application of Continuous Quality Verification to Pharmaceutical

and Biopharmaceutical Manufacturing Status: Overdue See WK46216 (TC: Claus Weisemann)

4. E2656-10 Practice for Real-time Release Testing of Pharmaceutical Water for the Total Organic Carbon Attribute Status: Ballot Action Required

5. E2810-11e2 Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units Status: Review for Ballot

6. F838-05(2013) Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration See WK43140 (TC: Russell Madsen)

E55.04 General Biopharmaceutical Standards 1. E1564-00(2014) Guide for Design and Maintenance of Low-Temperature Storage

Facilities for Maintaining Cryopreserved Biological Materials 2. E1565-00(2014) Guide for Inventory Control and Handling of Biological Material

Maintained at Low Temperatures 3. E1566-00(2014) Guide for Handling Hazardous Biological Materials in Liquid Nitrogen 4. E2097-00(2014) Guide for Determining the Impact of Extractables from Non-Metallic

Materials on the Safety of Biotechnology Products 5. E2888-12 Practice for Process for Inactivation of Rodent Retrovirus by pH

E55.91 Terminology

6. E2363-14 Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry See WK49054 (TC: Martin Warman) Ballot E55 (15-01) Item 001

mailto:[email protected]?subject=WK41265






E55.04 Draft Standards Extractables and Leachables

1. WK43975 Practice for for determining and characterizing extractables from materials used in single-use applications (TC: James Bray) Ballot E55.04 (14-03) Item 001;

2. WK48084 Practice for Determining and Characterizing Leachables released from Materials used in Single-use Systems under bioprocess operating conditions (Technical Contact: Alain Pralong)

Viral

3. WK39883 Practice for Process for Inactivation of Enveloped Viruses Using Detergent (Technical Contact: John Schreffler) Ballot E55.04 (15-01) Item 001;

4. WK43739 Practice for Process to Remove MuLV Virus by Filtration (TC: Robert Steininger II)

5. WK47635 Test Method for Determining Retention of Large Viruses by Membrane Filters Used in Aqueous Liquid Filtration (Technical Contact: Robert Steininger II)

6. WK47636 Test Method for Determining Retention of Small Viruses by Membrane Filters Used in Aqueous Liquid Filtration (Technical Contact: Robert Steininger II)

7. WK47637 Practice for Enumeration of PP7 Bacteriophage (Technical Contact: Robert Steininger II)

8. WK47638 Practice for Preparation of PP7 Viral Stock (Technical Contact: Robert Steininger II)

9. WK47639 Practice for Enumeration of PR772 Bacteriophage (Technical Contact: Robert Steininger II)

10. WK47640 Practice for Preparation of PR772 Viral Stock (Technical Contact: Robert Steininger II)

SUS Integrity and Characterization

11. WK47357 Practice for Application of Single-use System in Pharmaceutical and Biopharmaceutical manufacturing (Technical Contact: Alain Pralong)

12. WK43741 Practice for Testing Integrity of Single-Use Systems at Vendors Manufacturing Facilities (TC: Alain Pralong)

13. WK47355 Practice for Controlling Integrity of Single-Use Systems during Biopharmaceutical manufacturing process at End-user factory (TC: Alain Pralong)

14. WK43742 Practice for Characterizing Particulate burden from Single-Use Systems for End-user Impact Assessment (TC: Patrick Evrard) WK47356 Practice for Characterizing Particulates Burden from Single-Use Systems at Vendor Factory (TC: Patrick Evrard)

Biocompatibility

15. WK48956 Practice for Biocompatibility of Single-use System at End-user Factory (TC: Alain Pralong)

16. WK48957 Practice for Purity, Biocompatibility and Toxicity of Raw Materials used in the manufacturing of Single-use System (TC: Alain Pralong)






















48957 dard Practice Purity, Biocompatibility Toxicity of Raw Materials used in the ufacturing of Single-use System -

48956 dard Practice on Biocompatibility of le-use System

E55 Manufacture of Pharmaceutical Products meeting, 29-30 April 2015

Alain PRALONG in collaboration withPatrick EVRARD, and their SUTAP Team, Malik BELATTAR & Mathieu TRICOT

enda

andards use: Pair concept

ope

URITY BIOCOMPATIBILITY AND TOXICITY OF RAW MATERIALS (SUPPLIER)andard Key Elements

k and Biocompatibility Assessments: Critical Aspects

OCOMPATIBILITY OF SUS (END-USER)andard Key Elements

compatibility Testing Methodology

ded value from ISO 10993 and USP <1031>, <87>, & <88>

29 – 30 April 2015, ASTM, Lisbonand his SUTAP team – P.EVRARD, GSK VACCINES

ndards Use: Pair Concept

r Concept:Suppliers: WK48975: Assess the purity and toxicity of Raw materials used to manufacture Single-use SystemsEnd-users: WK48956: Ensure and maintain the biocompatibility of SuS throughout th(bio)manufacturing process flow

erarching guide: concepts of WK46541 applied to both Suppliers and End-users standards

ucture/Composition both based on E2500 approach and follow main stream

andard Practices: Provide “guidances” approach, not a description of Test Methods to perfo


WK48957 –

PURITY, BIOCOMPATIBILITY and TOXICITY of RAW MATERIALS (SUPPLIERS)


aw Materials & Biocompatibility for Suppliers

tandardized approach to:–Assess the purity and toxicity of raw materials–Detect non-specific, biologically reactive, physical or chemical characterist

of raw materials–Describe and characterize the biocompatibility of raw materials used to

manufacture SuS

cope


andard Key Elements

e risk assessment: provides critical criteria definitions of biocompatibility testing

scription of SuS manufacturing process operations from sourcing of raw materials to rilization of SuS components

scription of test matrix for biocompatibility assessment with regard to the type and plication of SuS components

ppliers have the responsibility to perform Biocompatibility test provide SuS with appropriate Biocompatibility certification


sk & Biocompatibility Assessments: Critical pects

S Critical Process parameters:

Contact and Surface time

Static or dynamic (flux)

Porosity/permeability

Temperature / pH / Pression

Structural parameters (gravity, density, shear strength, brittleness)

• Critical Aspects of Biocompatibility Assessment:

– Resin characteristics

– Critical Extrusion process parameters

– Critical parameters of assembling

– Films and bags specification

– Sample selection and testing

– Freezing and thawing characteristics


sk & Biocompatibility Assessments: Critical pects

uality by Design approachEstablish film & bag Critical Quality Attributes

Validate resin specifications process parameters that meets CQAs

Control established resin specification, process parameters and CQAs

Develop a life cycle approach for continuous process improvement & change control


WK48957 –

BIOCOMPATIBILITY OF SUSAT END-USERS FACTORY


ope

utline the ability of SuS to be in contact with a process fluid without causingny adverse effects on– Living systems– The quality and the safety of Intermediate Products– The Active Pharmaceutical Ingredient– The Final Product– Process Performance

rovide a standard risk based approach

ocompatibility for End-users


andard Key Elements

sk and science-based approachachables study: the basis of toxicology assessmentMust be correlated with Biocompatibility assessment results performed and documented by supplier

rong collaboration and communication between End-user SME and SuppME

Quality auditQuality Management System

ug product manufacturing processEnd-user process flow; Cell culture growth assessmentRisk assessment; List of CQAs from the Quality Target Product ProfileCritical Aspects of SuS BiocompatibilityQuality by Design Approach


ocompatibility Testing

nd-usersdo not have the responsibility of performing Biocompatibility testing

should used the limited information they receive

ell Line Selection for Biocompatibility Testif the cell line selected by end-users is different from those used by Supplier when performtheir Biocompatibility test, the end-use must proof the similarity/comparison (comparabilitytheir selected cell line with standard/typical cell line.

Otherwise, it is the responsibility of the end-user to test the biocompatibility of supplied Sumaterials with their own cell line/drug products. Regulatory body may request further information/documentation about this Biocompatibility testing


dded Value from ISO 10993 and USP <1031>, 7>, <89>

ell culture tests with growth performance

tandardized biological tests

Maintain the « Biocompatible » state throughout the whole life cycf SuS


Contacts:

• Alain PRALONG, SUTAP Director

• Patrick EVRARD, Senior Manager Disposables

• Malik BELATTAR, SUTAP Director Deputy

• Mathieu TRICOT, Project Engineer in Biotech Compliance

i f @ t

Do you have any questions?

Thank you for your attention

[email protected]

[email protected]

[email protected]

[email protected]

dard Practice for testing integrity of single-use ems - WK43741 dard Practice for Controlling Integrity of e-Use Systems during Biopharmaceutical

ufacturing process at End-user ry - WK47355

E55 Manufacture of Pharmaceutical Products meeting, 29-30 April 2015

Alain PRALONG in collaboration with Patrick EVRARD, and their SUTAP Team, Malik BELATTAR & Mathieu TRICOT

enda

ndards use: Pair concept

requisite

pe

RTICULATES FROM SINGLE-USE-SYSTEMS SUPPLIER FACTORY

ndard Key Elements

cal Aspects

RTICULATES FROM SINGLE-USE-SYSTEMS END-USER FACTORY

ndard Key Elements

cal Aspects

MMON TO SUPPLIER AND END-USER ANDARD

• Key Concepts

• Requirements, Specifications & Risk Analysis

• Testing Procedure & Methods

• Supply Chain

• Failure Management

• Verification, Acceptance Criteria

• Visual Check

29 - 30 April 2015, ASTM, Lisbond his SUTAP team – P.EVRARD, GSK VACCINES

ndards Use: Duet Concept

et Concept: Testing Integrity/Leak DetectionWK43741: Address Testing Methodology to be adopted by SuppliersWK47355: Address the Control and Maintenance of Integrity/“Leaks Free” and approach to implement by End-users

erarching guide: concepts of WK46541 applied to both Suppliers and End-users standards

ucture/Composition both based on E2500 approach and follow main stream



requisite

y Notion from precedent ASTM E55 meeting

29 - 30 April 2015, ASTM, Lisbon

Mapping of (Bio)pharmaceutical Product Mfg Process

System / Component after Filtration = 0,22 µm

No

Yes

Detailed Risk Assessment

• List SuS systems - WC Scenario regardprocess• (Bio)pharmaceutical manufacturer capaensuring SuS integrity• Define verification / routine testing stratensure SuS integrity pre and/or post-usefinal sterile filtration:

•Direct testing (physical)•Indirect testing (microbiological)

Selection WC ProcessManage

Business risk

d his SUTAP team – P.EVRARD, GSK VACCINES

ope


• Criticality of Filters (bacterial retention) anContainers (long time and large contact surfaces, leak appearance increased)

• Compromise SMI that may impact producquality and patient safety

• Applicable to new and existing SuS

• Applicable to implementation of change toexisting SuS + Continuous improvement during operation

Suppliers End-users

Applicable from concept to retirement

andardized approach to test the egrity/leak detection

sed on a risk assessment and SMI

B to be considered with intended use

B contribute to maintain integrity based SMI

MI and SBB considered as CQAs


INTEGRITY FROM SINGLE-USE-SYSTEMS AT SUPPLIER FACTORY


e overall objective is to define supplier manufacturing capability to produce SuS product meetinined quality requirements and ensuring the SMI or SBB

e approach described within this practice is compatible with continuous improvement of nufacturing capability and enables SuS manufacturing innovation

e key elements of this practice are:

A description of risk assessment and testing definition process,

A description of the testing procedures,

A description of the required supporting SuS manufacturing processes

his practice is intended to satisfy quality requirements for design in ensuring integrity of SuS at upplier manufacturing facility with regard to SMI or SBB


andard Key Elements


tical Aspects of SuS Integrity are typically functions, features, abilities, and performance or aracteristics necessary for the SuS manufacturing process to ensure SMI or SBB

tical Aspects must be identified and documented based on scientific product and process derstanding.

portance of Critical Aspects increase from one step to the next during the manufacturingS

tical Process Parameters (CPPs) related to these critical aspects must be defined at each d must be determined during development stage


tical Aspects


INTEGRITY FROM SINGLE-USE-SYSTEMS AT END-USER FACTORY


s practice describes a systematic, efficient, and effective way of ensuring and maintaining egrity of SuS with regard to SMI or SBB

e End-user must consequently manage risk to product quality and patient safety through thcess validation and continuous verification program.

e key elements of this practice are:

escription of the validation of SuS integrity,

insurance that SuS integrity is maintained,

ability to a post-use testing to validate the integrity of SuS as alternative,

End-user must implement SuS that are fit for intended use, with regard to critical aspects


andard Key Elements


tical Aspects of SuS Integrity are typically functions, features, abilities, and performance or aracteristics necessary for the manufacturing process Ensure consistent product quality and patient safety with regard to SMI or SBB

s practice must consider filters and containers as the most critical components of SuS Level of Criticality depends on critical steps related to microbial contaminations

erification activities must focus on these aspects of SuS and must be documented


tical Aspects


COMMON TO SUPPLIER and END-USER STANDARDS


y Concepts

erile Filtration (commonly 0,22 µm)Cut-off, bacterial retentionCheck the relative position of SuS to be assessed with regard to Sterile Filter (before or after)

uctural and Mechanical Integrity (SMI)Physical properties of SuSIntended use (bio-containers, bioreactors, bulk storage, media storage,…)

• Tightness– Inherent properties of films (MoC) and b– Direct relation with integrity/leak appeara– Related to Porosity and Gas Permeabilit

characteristics

• Sterile and/or Biosafety Barriers (SBB)– Free from microbiological contamination

safety of operators (product/fluid leaks)– Direct impact on SMI, contribute to main

sterility/integrity– Key notions for the intended use (protec

of product and operators)


quirements, Specifications, and Risk Analysis

requisite: SuS Manufacturing Process knowledge,

SuS Manufacturing Process environment control,

SuS Raw Material of Construction knowledge,

Operators and inspectors trainings, and

User Requirements Specification (URS) from end-user if applicable.

ntainers risk: leak testing and control in the limit of detectability and testing feasibility.Leak sensitivity is ranged from Ultra-fine to Fine leaks per F2391.

Containers risk must include transportation and storage condition, freezing and thawing process wheapplicable.


quirements, Specifications, and Risk Analysis

anufacturing system risk: leak testing and control

Leak sensitivity is ranged from Fine to Large leaks per F2391

Manufacturing system include but are not limited to: films and welding

sembly risk: leak detection (visual check) method and control, and considered atferent stage of the SuS lifecycle such as overfill, mixing, handling, and shipping

Leak sensitivity is ranged from Moderate to Large leaks per F2391.

Assembly hazards must include but are not limited point of puncture, wear, stress, misuse


ting Procedure & Methods

sting Methodology

Checklist of Testing: define a plan for testing developed by supplier and approved by end-user prior to execution

Materials to be tested• Type of materials (MoC)• Size of components• Fluid contact surface area• Complexity of materials• Sterilization process• Transportation and storage conditions• Intended use


- Setting and parameters• Limit of Detection• Sensitivity• Robustness• Repeatability/Ruggedness,

and• Applicability

- Type of Integrity Testing• Leak Integrity• Seal Integrity• Others (special cases)• Correlation between physical

and microbiological testing


pply Chain

pplier documentationCertificate of GEP/GMP complianceCertificate of irradiation/sterilizationValidation report/Validation bookCopy of test resultsCertificate of Analysis

• Integrity/Leak detection tests• Training of operators

egrity Assurance must demonstrate and ensure the maintenance of integrity/leak free stateoughout the lifetime of SuSPackaging and Sterilization is ensured and under the responsibility of Suppliers


ure Management

ilure TypeDefects and Physical AlterationIntegrity breach/Microbiological contamination

anagementInternal or external complaints and deviations

termination of failureFailure typeSizeShapeInspector’s level of expertise and experience

vestigation must be performed, and follow writing instructions (SOPs)


fication, Acceptance Criteria

llow Verification strategy, Verification Activities, Verification Review and Acceptancd Release of ASTM E2500

ceptance CriteriaLeak dimension• Pinhole equivalent• Equivalent channel

Leak flow rate• Differential pressure• Refer to E2095, define and measure leak flow rate test parameters


ual Check & Reporting

ee of any visible defect that can impact SMI of SuSImplemented prior to each stage of the manufacturing processCheck on material, equipment and the environment of workTrained person (≠person involved in the preparation or manufacturing of SuS)Criteria defined and validated during development of SuS

portingKeep record of test results of integrity/leak detection testing (Certificate of IntegrityFrequency: at least annually or after critical change, published or available to the certification notified body or its representative


Contacts:





i f @ t



[email protected]

[email protected]

[email protected]

[email protected]

WK43975: “Standard practice for determining and characterizing extractables from materials used in

single‐use applications”

Status & Path Forward

J Bray, B Steininger, J Vogel

April 29, 2015

1

Ballot 1• Submitted to ballot mid December 2014

• Based significantly on BPOG developed publication – “Standardized Extractables Testing Protocol for Single‐Use Systems in Biomanufacturing” W.

Ding, et. al, Pharmaceutical Engineering, November / December 2014– Testing of wide range of components– Solvents – 6 mandated– Pre‐treatment conditions– Extraction conditions & times– Analytical methods– Reported data – standardized formatting

• Modifications based on input received from suppliers and 3rd party testing labs– Tiered vs. mandated 6 solvents; change in one solvent– Test intervals– Allowance for options elected & justified by supplier

• Written as a Practice – Do this and you can use the results for following purpose– However, language of the scientific article remained creating confusion and comments

Convergent Consulting, LLC 2

Ballot 1 Results

• Ballot closed January 16, 2015• Statistics


Ballot 1 Comments

• 37 sets of comments received ; total of 474 comments.

• 5 categories of comments – color coded for degree of difficulty green – pink ‐ red– Editorial

• e.g., make the procedure more prescriptive, focused, more like a Practice vs. an article; references • Readily addressable

– Terminology• Not without difficulty given the tendency to blur terminology in the Extractables / Leachables area.• Authors believe a laser focus on just extractables and harmonizing on new ASME – BPE terminology

will resolve this.

– Extraction solvents– Testing time points

– Analytical methodology – Lot of input from objective 3rd party testing labs• Significant % of comments focused on this.• Some complexity as there are interactions with some of the specific solvents recommended and

analytical methods• Should be resolvable once the types of solvents are clarified; albeit Practice may require some

flexibility in adjustment of analytical methods.

4Convergent Consulting, LLC

Significant departure betweensuppliers and end users}

Path Forward• Major gap is significant disagreement between end users

(BPOG) and suppliers (BPSA) over solvent and extraction times

• If no room for compromise; no potential for successful ballot

• Gathered small working Group of 9 (Go9) to see if there is room for compromise


ASTM BPSA BPOG

J BrayB SteiningerJ Vogel

J Anant EMD Millipore

R Acucena GE

J St. Laurent Chemic Labs

W Ding Amgen

E Mahajan GenentechK Wong Sanofi Pasteur

Path Forward (cont’d)• Go9 phone conference March 27

• Discussion focused on red issues of solvents and extraction times– BPSA had proposed round robin testing program; BPOG not responsive to proposal

– Drafted compromise language around solvents acceptable to Go9

– Recognition of required changes in analytical methods; not simple

• Solvent compromise language presented to BPSA Board w/o April 20 and got thumbs up to proceed


Path Forward (cont’d)

• Split into 2 practices: “Standard practice for determining and characterizing extractables from materials used in single‐use applications: …– Part 1 – Preparation of Extractables Test Solutions” – Part 2 – Analysis of Extractables Test Solutions”

• Drafting of Part 1 by 3 ASTM reps of Go9 in progress


Milestones

• Part 1 ready for ballot mid‐June– Allowances for flexibility in modifying conditions of Practice if sufficient scientific rationale can be provided

– Put onto WK43975 ASTM Workspace mid May– Review by Go9 mid May– Obtain buy in from BPSA and BPOG end May– Ready for ballot mid June

• Develop strategy for drafting Part 2 end of May– Will require SME equivalent of Go9 to be convened


UPDATE: Triton X-100TM Detergent Inactivation ASTM Standard:

Work Item WK39883

John SchrefflerEisai, Inc.

29April2015

2

• Standard Background• Ballot 1 Review• Working Group 2 / Updated Specifications• Future Work• Ballot 2 Review

• Negatives• Comments

• Future Plans

OUTLINE

3

• ASTM WK39883, 55.04• Standard Practice for Process Step to Inactivate Rodent

Retrovirus with Triton X-100 Treatment• Main Purposes of Standard is to Provide Robust standard

practice that ensures patient safety• Regulatory Relief (lower costs of viral validation early phase)• Along with other standard practices, (low pH Viral Inactivation

and Viral Filter), this standard can be used in early stage clinical trials (Phase I or Phase II) to ensure viral safety

• Could be beneficial to Hospital / University / Small Company for Phase I studies

ASTM Triton X-100 Detergent Inactivation Standard Brief Overview

4

• Small working group was formed to generate the first draft of this standard

• Balloted on 24MAR2014• Received:

• 2 negative votes• 17 affirmative votes• 11 abstained• 3 affirmative with comments• Additional comments from 2 SMEs

ASTM Triton X-100 Detergent Inactivation Standard First Ballot

5

• Amgen, Genentech, Pfizer, Eli Lily, Biogen Idec, Eisai• All specifications were reviewed for robustness• Certain specifications were deemed unnecessary• Other specifications were discussed for validity• Enough data were available to remove the mixing time and protein

concentration specifications from the standard• Enough data were available to not include lipid concentration and

total protein concentration as specifications

Following Ballot 1, a second group was formed from experts from across the industry

6

• For this standard practice the key parameters specified:• Triton X-100 concentration• Hold time• Inactivation temperature• Mixing time• Monoclonal antibody or fusion protein concentration.

Ballot 1 had the following parameter specifications

7

• Current specifications in the new draft are:• Triton X-100 concentration• Hold time• Inactivation temperature• Mixing time• Monoclonal antibody or fusion protein concentration.

The updated draft NOW has the following parameter specifications

8

• Balloted on Feb2015• Received:

• 3 negative votes• 4 affirmative with comments• 2 Abstain with comments

ASTM Triton X-100 Detergent Inactivation Standard Second Ballot

9

• Nathan Roth – CSL Behring• Section 1.2, Section 3, Section 4.2: pH is not addressed. An

acceptable pH range should be addressed, or discussed in section 3 why not applicable

• Section 4.3.1: Better definition of "clarified cell culture" is required.

• Aggregates could protect virus from inactivation. Minimum nominal clarification filtration size should be provided, or the product should be filtered through a defined nominal pore size filter prior to SD, or justification provided in Section 3 shy this is not required.

• See attachment for additional suggestions to standard.

ASTM Triton X-100 Detergent Inactivation Standard Second Ballot Negatives

10

• Christian Menzel – EMD Serono• Unclear what the purpose of the standard is. Rational to make

manufacturer studies obsolete for viral inactivation in the context described?

• If so, all examples cited are referring to mAbs only. Where is the evidence that this equally applies to Fc fusion proteins? However no detailed review of the cited literature was made.

• Avoid using trade names for the chemical components even if more familiar for the scientific community.


11

• Jeffrey Carter - GE• My primary concern is putting some boundaries around salt and

pH.• For the authors to consider - is the discussion point on line 125

possible to misconstrue to mean that the procedure is claimed to be effective against adventitious viruses?

• Line 212 – Lilly?


12

• Janmmet Anant – EMD Millipore• Overall, I approve the document; however, I understand that

Triton X-100 is on its way to being outlawed for use, at least in Europe, so I'm puzzled about the timing for this.

• Norbert Schuelke – Millenium Takeda• Additional detergents to add, ATPE to harvest type, corrections

• Anastasia Lolas – Visionary Pharma Consulting• Corrections

• Jerold Martin – Pall• Use of Triton X-100 in standard, editorial

ASTM Triton X-100 Detergent Inactivation Standard Second Ballot Comments

13

• Future plan is to send e-mail to commenters following this meeting and work on acceptable changes to draft

• Some data are already available to support second ballot (fusion proteins), but I will continue to work with the SMEs from other companies to ensure this standard contains robust specifications

• Submission of third ballot will not be performed until all comments can be successfully addressed with commenters

• Next ballot would also ask for feedback from regulators on final draft (had FDA input, needed PEI, Hannelore W.)

• Possible dates for third ballot include date of reaching compromises with commenters or after Viral Clearance Symposium (Biogen – Oct.)

• Finally, the inclusion of additional detergents will also be discussed with other companies at this symposium (NOT for third ballot)

• Hope would be to include additional detergents if this makes sense (ie no i.p. on newer detergents) in future version of standard

Path forward for this standard

andard Practice for Characterizing articulate matter from Single-Use Systems for nd-user impact assessment - WK43742andard Practice for Characterizing

articulate Matter from Single-Use Systems at upplier Factory - WK47356

Patrick EVRARD in collaboration with Alain PRALONG and his SUTAP Team, Malik BELATTAR & Mathieu TRICOT

E55 Manufacture of Pharmaceutical Products meeting 28-30 April 2015

da

dards use: Pair concept

Principle

rences and Use

Scale and USP Categorization

RACTERIZING PARTICULATE MATTER FROM GLE-USE SYSTEMS AT SUPPLIER FACTORY PPLIERS)

e

cal Aspects

ufacturing Process

le particulates - Visual Check as IPC

RACTERIZING PARTICULATE MATTER FROM GLE-USE SYSTEMS FOR END-USE IMPACT ESSMENT(END-USERS)

e

• Critical Aspects

• Visible particulates - Visual Check as IPC

• Manufacturing Process

• Risk Assessment

• SUPPLIERS AND END-USERS INFORMATION EXCHANGE

• Supplier Assessment

• Certification

• Capability - test method validation

• Routine Control

• CONCLUSION

ollaboration with SUTAP Team 29 – 30 April 2015, ASTM, Lisbon

dard Use: Pair Concept

air Concept: – END-USER : WK43742: Perform a particulates matter risk/impact assessment based

Supplier process capability data– SUPPLIER : WK47356: Perform a particulates matter risk assessment based on

particulates specifications with regard to process capability

verarching guide: concepts of WK46541 applied to both Suppliers and End-users standard

ructure/Composition both based on E2500 approach and follow main stream


29 – 30 April 2015, ASTM, Lisbonollaboration with SUTAP Team

Principle

eminder from previous ASTM E55 meetingarticulates risk/impact assessment

upplier :– Certifies cleanliness Level of SuS

• Based on Mfg process understanding, including particulates levels capability

ser :– Biopharm Manufacturing Process Mapping– Risk/impact assessment


Principle

eminder from previous ASTM E55 meeting – e.g. sub-vis particulates

cation

cess pping

S in contact id path

& Impact ssment

SuS Supplier Manufacturing Capability

and Certification

SubVis Specification on (Bio)pharmaceutical Product

Supplier Certification

No

Yes

Flowsheet of Mfg Process

System / Component after Filtration ≤ 10 µm


No

Yes


• List SuS systems - WC Scenario re. Mfg• SubVis particles contamination* in Final x% of SVP specs

• 1 test for SubVis particles in Qualificatiosystem (or equivalent)

Based on - actual data- audited and apprmonitoring practic- operations under(classified mfg are


ence and Use

TM:E2281 Practice for Process and Measurement Capability Indices

O Standards: ISO 14644 Cleanrooms and associated controlled environment

ernational Conference on Harmonization: ICH Q4B Annex 3 (R1) Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Particulate Contamination: Sub-Visible Particles General Chapter

• United States Pharmacopoeia:– USP <787> Sub-visible Particulate Matter in Protei

Injections– USP <788> Particulate Matter in Injections– USP <790> Visible Particulates in Injections

• European Pharmacopoeia:– EP 2.9.19 Particulate Contamination: Sub-Visible

Particles– EP 2.9.20. Particulate Contamination: Visible Partic

• Japanese Pharmacopoeia:– JP 6.06 Foreign Insoluble Matter Test for Injections– JP 6.07 Insoluble Particulate Matter Test for Injectio– JP 6.08 Insoluble Particulate Matter Test for

Ophthalmic Solution


Scale and USP Categorization

mit between visible and sub-visible domain – Based on scientific practices for consistent human visual inspection– Commonly accepted limit is 100 µm with 70% detection probability

ollaboration with SUTAP Team

WK 47356 CHARACTERIZING PARTICULATE MATTER FROM SINGLE-

USE SYSTEMS AT SUPPLIER FACTORY- SUPPLIERS -


e

pplicable to all product path components of pharmaceutical and biopharmaceutical Single-uystems used for parenteral applications

upplier’s actions to– design– validate– keep their manufacturing process under control (“remain in validated state”)– certify SuS particulate level (“particulates performance”)

• with proper set of info– improve process through continuous improvement initiatives


al Aspects

Critical characteritics of particulates:– size– quantity– shape– identity– source– toxicity– and process capability

Out of consistency considered as an indication of process out of control


facturing Process

Suppliers are responsible to design a “clean” process and keep it under control : – SuS manufacturing environment conditions and controls

» ISO 7/Class 10,000 in operation - Grade B (ISO 14644-1, FDA cGMP, EU cGMP)

– Clean entries in manufacturing area (material, people, tools)» Specs, controls, sub-suppliers mfg process, …

– Clean Manufacturing process (vibrating steps, intermediate cleaning steps, …)» Packaging operations and materials

– Particulates generation in compliance with intended use (such as mixer, …)– Monitoring, with validated extraction and measurement methods– Eventually, intermediate cleaning steps

» Contact / non-contact, dry/liquid

– Process understanding and continuous improvement


e particulates - Visual Check as IPC

sual Check– to locate and identify particulates during SuS manufacturing process

• often with light tables (or similar)• particulates size comparison charts and other analytical relevant test methodsmagnification procedure can be applied to enhance the probability to detect particulate

• to be recorded and statistically followed

articulates Catalogue : – based on particulate characteristics, with associated average occurence


WK 43742 CHARACTERIZING PARTICULATE MATTER FROM SINGLE-

USE SYSTEMS FOR END-USE IMPACT ASSESSMENT- END-USERS -


e

pplicable to all product path components of pharmaceutical and biopharmaceutical Single-uystems used for parenteral applications

nd-users shall:– Perform a particulates risk assessment for SuS used in Biopharm process

– Risk-based and science-based approach to particulates risk/impact assessment of SuS

– Perform a description of the risk/impact assessment, derive particulates specifications frothis impact assessment, and apply a verification approach

– Define the routine processes ensuring maintenance of the SuS in its qualified state

– Risk is associated to the route of administration and the likelihood of SuS Component-Dosage form interaction with regard to particulate matter


al Aspects

Particulates size, quantity, shape, identity, source, toxicity, and process capability; scientific product and process understanding

End-users should be responsible for :

– Biomanufacturing environment classification; associated cleanrooms design

– Operators gowning and handling

– Training

– Biomanufacturing process design, with characterised particulates emission performance (e.g. spallation)

– Biomanufacturing particulates removal systems/process steps


e particulates - Visual Check as IPC

nd-users: – by trained person (operator) and must be appropriate with the nature of the SuS inspecte

and the point of use


facturing Process

d-users:Prepare the process flow sheet (existing or new process),Evaluate if SuS are used and where it should be use,Identify Particulate clearance stages,Identify Worst case scenario, and Select SuS which allow to respect limits of particulate matter with regard to process flow sheet (Risk/Impact assessment)

rticulates MitigationPurification, Rinsing, Clarification, Precipitation, Sedimentation, Centrifugation, Filtration (including Ultra-Filtration and Dia-Filtration). A scientific justification must be provided to prove and quantify the particulates reduction during these steps

rticulates Catalogues: Based on particulate characteristicsIdentification step in order to minimize the risk given by a single or amount of particulates in the SuS


Impact Assessment – Sub-visible particulates

ceptance or set up mitigation plan


SubVis Specification on (Bio)pharmaceutical

Product


No

Yes

Flowsheet of MfgProcess



No

Yes


• List SuS systems - WC Scenario re. Mfg process• SubVis particles contamination* in Final Container < x% of SVP specs

• 1 test for SubVis particles in Qualification on SuS system (or equivalent)

Based on - actual data- audited and approved monitoring practices- operations under control(classified mfg areas)

Impact Assessment - Visible particulates


Mapping of (Bio)pharmaceuticalProduct Mfg Process


No

Yes


• List SuS systems - WC Scenario re. Mfg process• (Bio)pharmaceutical manufacturer capability for visible particulates burden• Visible particulates contamination* from SuS may not impact significantly (Bio)pharmaceutical manufacturer capability (process capability and consistency limits)

Selection WC Process

Supplier AQL

NB : AQL per type of particle

Based on - actual data- audited and approvedmonitoring practices- operations under control(classified mfg areas)

* taking into account particles reduction further to process steps (i.e. purification, rinsing ...) if scientifically provenProcess steps likely to generate particles (i.e. mixing) must be assessed

SUPPLIERS AND END-USERS INFORMATION EXCHANGE


ier assessment

nd-user verifies evidence of: – Acceptable supplier quality system,– Supplier technical and process capability, – Supplier application of Good Engineering Practice (GEP) and current Good Manufacturing Practice

(cGMP)– Adequate test or examination method(s) used, limits of the test or examinations, and actual results

the tests or examinations• Based on end-user’s assessment, verification tests may be needed or not (1-time or periodic)

nd-user :– Quality control personnel of End-user review and approve the documentation setting forth the basis

qualification (and re-qualification) of any supplier,– Maintain documentation of Supplier qualification


ficationVisible Particulates/Visible Particulates

ertificate of Analysis (CoA)– Reference to test method, limits and actual results of the tests or examinations– End-user releases the SuS based on supplier’s CoA data

b-visible:– Applicable to the 2 classes of particulates described in the Pharmacopoeias

• particulates ≥ 10 µm• particulates ≥ 25 µm

– When certification conforms with Large Volume Parenteral (USP <788> or equivalent), additional data to supplied:

• Applicable acceptance criteria, depending on the method used to measure the particulates level, and• Volume of flushing solution used to collect the particulates

sible: – Certification must be based on manufacturing capabilities established by routine monitoring control– Specify this quantity via AQLs (recommended)– Supply a catalogue of known visible particulates with their critical aspects


bility - test method validation

oven manufacturing process capability must be available to support Particulates certification

articulates flushing data, from routine sampling, must be supplied to end-user

ata must be generated by testing performed under GLP conditions:– The flushing method must be defined in details, and properly documented.– The recovery efficiency of the flushing method must be validated, or it must be scientifically

demonstrated that the flushing method collects the majority of particulates present in the SuS comply with the ‘Essentially free’ state.

e particulates measurement method must be validated. Methods described in USP <788> (Ligbscuration Particle Count Test and Microscopic Particle Count Test) are the reference methods

used. Other methods can be considered providing a correlation with one of the above methodd has been validated


ne Control

dequate monitoring and control program to support SuS manufacturing capability– Routine compliance to certified particulates level

upplier’s operations under control, in activity classified manufacturing environment ISO 7

0% visual check by trained operators (if applicable)

case Visible particulates found in the system (fluid path), SuS should be discarded

outside of specification (AQL), return to supplier and complaint raised


CLUSION

ollow an E2500 approach: Specification, Risk/Impact Assessment, Qualification, and Routinontrol– risk-based and QbD approaches

air concept allow a better and clearer use of these standard practice– Allow a better understanding of perimeters of activities and responsibilities

hese 2 practices– provide a simple and understandable way of performing Particulates / Risk Assessment

throughout all stage of SuS manufacturing operations, supporting implementation in GMPapplications

– enable clearer and more transparent communication between Suppliers and End-users and each other Roles & Responsibilities


Contacts:





i f @ t



[email protected]

[email protected]

[email protected]

[email protected]

GEA Process Engineering / GEA Pharma Systems

Trevor Page

Continuing the Continuous

GEA Pharma Systems / GEA Process Engineering

• Standard in Development for many years !!• Multiple Ballots and extensive revisions • More detail … too prescriptive • Less detail … not specific enough • Chemical / process engineers ..we don’t need this detail • Pharmacists / Chemists …this is too complex

• October 14 last ballot of Wk Item

• Outstanding negative withdrawn subject to agreement to start revision 2 of standard after publication

Background


• Outstanding Negative comments

• The standard is written from the view point of an automation/controls engineer and does not reflect Process Control within a Pharmaceutical manufacturing environment, where control is built upon Process Design, Process Validation and Continued Process Verification. “Control maybe King” in other industries but within Pharm the focus is on Quality by Design, and then controlling the process to ensure product quality. There is no reference to Where, What, When, Why or How to control.”

Background


• Choices :

1. Start a revision of the standard

2. Consider putting details in to a lower level standard

Next steps


• Clarify specifics of :

Where, What, When, Why or How to control

• Determine what level of detail is possible in a standard • Break down into smaller sub / child standards ( 1 or more )• Create the smaller child standards “quickly” • Publish child standards • Modify main standard to reference new standards

Propose key task group members :

Don Kientzler , Martin Warman + ????????

Proposed direction

DISCUSSION TOPICS

History

New Standard’s Scope

Outline

2

ORIGINAL DOCUMENT

Discusses considerations for sampling in PAT environment

Not prescriptive- considerations only

Does not address sampling plans

Does not address statistical considerations

3

REQUEST FOR A NEW DOCUMENT

FDA

Ali/Others

Intent was for a Standard Practice

4

SCOPE

Scope:The proposed standard Practice will provide the industry with

guidelines to support the development and implementation of a robust sampling plan as well as guidance on individual sampling practices. This will provide guidance to industry and regulatory bodies on the appropriate considerations, development, scope, elements and implementation of a sampling plan in support of all stages of process development and verification.

.

5

CHANGES

Two part document:

Part I – Sampling plans

Part II- Sampling considerations

Part iii?? – basic statistics

6

PART I – SAMPLING PLAN

Master Sampling PlanWhat & Why being sampled must be explained HowStatistical Validity of samplePhysically valid sampleRisk Assessment

Sub Plans - Focus will change as we move from stage 1 to 3.

7

FUNDAMENTAL ISSUE

C O M M I S S I O N I N G A G E N T S , I N C . 8

SUB PLAN – PROCESS DEVELOPMENT

Gaining process & product knowledgeLittle Risk to patient, risk assessment focus is on

increasing knowledgeDetermine appropriate sample mechanismsPhysical relationships Chemical relationships

9

SUB PLAN – SCALE UP

At Scale sampling studiesStatistically valid – oversample ? Physical effectsTime dependenciesRisk assessment focus on Patient safety.

10

SUB PLAN- COMMERCIAL PRODUCTION

Risk Based – Focus on patient safetyProcess ControlGaining Process knowledgeAcceptance criteria statistically based Long term analysis and studies.

11

SAMPLING CONSIDERATIONS

Based on Original standardBalloted several timesShould be close to acceptableNew voting members means new comments

C O M M I S S I O N I N G A G E N T S , I N C . 12

Standard Guide for Specification, Design, Verification, and Application of Single-use Systems in Pharmaceutical and Biopharmaceutical Manufacturing

Duncan Low

Why a new standard?

• Single use applications increasing• Multiple drivers

• Traditional validation approaches impractical/impossible• No IQ/OQ• qualify a design and the supplier’s ability to deliver to it

• Reliance on the supplier increases significantly• Use of supplier’s data

• Transparency in supply chain, change control communication

• Transportation

2

Ballot status is positive

Sent Returned % returned

76 49 64.47%

3

Affirmative 27Negative 3

Abstain 19

% Affirmative 90

• Additional negatives in comments and sub-committee votes

• Negatives are being addressed

• All editorial corrections completed

• Focus has been on content • flow and avoidance of repetition can be improved

Negatives are being addressed

• Two negatives readily resolved

• Several overall affirmative votes had specific negatives• Addressing via direct contact or through collaboration site• All voters added to collaboration site

• Proposing to take a non-prescriptive tone• Should vs must

• Clarification on need for confirmation of supplier’s data

4

Discussion topics

• Moving away from imperative tone

• Verification of supplier’s documentation

• Leak or functional testing preferred to integrity

• Use of end user documentation dropped

• Reference to Annex 15

5For Internal Use Only. Amgen Confidential.

Next steps

• Rework to improve flow and close out comments• Please support on collaboration site

• Keep focus on ‘equipment like’ elements• Separate standards for E/L, particles• Closer alignment with leaks

• Re-ballot when remarks are addressed• Invite comments, update status at PDA SUS Workshop• Close out before Fall meeting

6For Internal Use Only. Amgen Confidential.

7

POLYMERS CONVERTING ASSEMBLY STERILIZATIONPACKAGING

SHIPPING

Supply Chain

Quality Variability

Technical TransparencyChange

Variability can arise at multiple points in the chain

Purpose designed materials provide superior performance

• First generation materials chosen on a partially empirical basis• USP Class VI compatibility, mechanical strength

• Improved understanding has led to the identification of additional quality attributes• Contribution of components and additives in multi-layer films

• Second generation films include these attributes in a qualified design space• Improved performance• Better management of change

ASTM ‐E 55.94Outreach & Education

Ferdinando Aspesi & Team

E55.94 – Phase IManagement & Senior KOL’s ‐ 1

• Status April 2015• Identified a population of 118 Companies and Consortia

• Contacted 65% of the ones assigned to the six members E 55.94 Team ( to be completed by 06/15).

• The list of the Companies where we don’t have a connection is attached

E55.94 – Phase IManagement & Senior KOL’s ‐ 2

• You need your help to find a contact for the following Companies:– Grifols– Esteve– Incyte– Mallinkrodt– Regeneron– Sun Pharmaceuticals– Valeant– Actavis

E55.94 – Phase IICurrent ASTM E55 Membership

• Current Membership – 199 members• A Letter with the ASTM E55 and the ASTM International Brochures will be sent to the members for educational info – 06/15

• A Survey will be electronically mailed to the Membership to provide a proper feedback from the membership on their experience and potential new areas of interests – 10/15

E55.94Team ‐ Acknowledgments

• Ferdinando Aspesi• Russell Madsen• Martin Warman• Duncan Low• Robert Steininger• Graham Cook• Christine DeJong

Documents

Schedule - astm.org · E55 Manufacture of Pharmaceutical Products Hovione - Lisboa, Portugal Schedule E55 Manufacture of Pharmaceutical Products Meeting Hovione Farmaciencia Sa -