White Paper –
Irvine Dry Powder Media Facility — Validation Harmonisation

Introduction

A new Dry Powder Media (DPM) manufacturing facility is in the process of being constructed and qualified at the existing SAFC Irvine, Scotland media manufacturing site. The addition of dry powder milling and blending capability to this facility will complete a 5-year Capital Expansion Plan SAFC initiated as part of its long-term commitment to supporting customers in the growing industrial biopharmaceutical market. The purpose-built facility will produce animal component free (ACF) media and will offer regional support to the European market along with manufacturing redundancy to its North American sister facility in Lenexa, Kansas.

The purpose of this document is to present details of the proposed validation strategy for the new facility and an overview of the harmonisation approach to ensure comparability with the Lenexa plant. This document is being issued in advance of formal qualification to facilitate review of the planned performance qualification (PQ) approach.

While there are no specific regulatory requirements which apply to the manufacture of dry powder cell culture media, it is the intention of SAFC to fulfil industry expectations in compliance with the relevant US FDA and EU legislation governing cGMP biopharmaceutical production to the extent appropriate to ensure product consistently meets specification. An overview of the regulatory references used can be found in the Validation Approach section of this document.

It is intended that the complete validation package will provide a high degree of assurance that the Irvine DPM facility can consistently produce product across the required operating range in accordance with documented User Requirement Specifications, Finished Product Specifications and cGMP. The validation package will also demonstrate equivalence of product with that produced at the existing SAFC Lenexa facility.

The new facility at Irvine is currently under construction with commissioning and qualification scheduled to start Q4 2013. The fully qualified facility will be handed over for routine manufacture during Q1 2014.

Facility Design Overview

The Irvine, Scotland DPM facility is designed for the validation, manufacture and packaging of ACF dry powder media batches from 25 - 6000kg. The facility will include:

  • New raw material and finished goods warehousing with temperature mapped and controlled storage areas that are continuously monitored via a new Facility Monitoring System (FMS).
  • New formulation suites to support product lot formulation from small to large scale. Formulation rooms are designed with humidity control and continuously monitored.
  • Two separate manufacturing lines
Line 1
Mill Type: Pin Mill
Pre-Blender: Conical, Auger Screw Blender
Post-Blender: Tumble
Batch Size: 750-6000KG

 

Line 2
Mill Type: Pin Mill
Pre-Blender: Tumble Blender (IBC)
Post-Blender: Tumble Blender (IBC)
Batch Size: 25-750KG

The tumble blenders in Line 2 will be able to operate with 200L, 1000L or 2100L IBC’s.

SAFC have many years extensive experience working with equivalent blending and milling technologies in our global operations.

  • Process rooms will be supplied by dedicated HVAC systems where appropriate, environmentally controlled and monitored via the FMS.
  • Validated cleaning processes for all equipment including Clean-In-Place (CIP) processes for fixed equipment and pipework, Clean-Out-Of-Place (COP) wash room and an automated IBC washer. All cleaning processes will utilize industry recognized CIP-100® and include a purified water final rinse followed with a defined drying cycle.
  • New Purified Water (PW) plant and distribution loop producing EP/USP grade PW.
  • Clean compressed air and clean nitrogen supply and distribution.

Validation Approach

All validation work will be carried out in accordance with recognised standards and guidance for the prospective validation of a new facility. This will include current Good Manufacturing Practice as defined in 21 CFR Parts 210 and 211, 21 CFR Part 11, EU Orange Guide, GAMP 5 and ISPE guidance on utilities, commissioning and qualification. These references are fully defined within the Irvine DPM Facility Validation Master Plan (V12-303-VMP).

Engineering studies will be carried out as a precursor to formal qualification. These studies will be used to develop the key process parameters that will be used during performance qualification (PQ).

Due to the level of flexibility required by the DPM facility it is not possible to exhaustively test the entire range of products and operational parameters. Qualification has therefore been designed using a risk based approach to define a range representative of routine use, for example using representative products and maximum/minimum operating parameters. High level details of the validation strategies for key activities are presented within this proposal.

Equipment Qualification

Equipment design and qualification will follow the principles outlined in recognized industry guidance documents, for example the ISPE baseline® guides. All equipment will be qualified to demonstrate compliance with approved User Requirement Specifications and cGMP.

The facility will be broken down into systems to facilitate qualification. Each system and component will be subject to an impact assessment to determine criticality. Criticality will be defined based on potential impact on product quality using the designations of direct, indirect and no impact. The level of qualification testing required will be determined based on these assessments.

Direct impact systems will be subject to formal design review, installation qualification (IQ) and operational qualification (OQ). Factory acceptance testing (FAT) and site acceptance testing (SAT) will be carried out on major items of equipment where appropriate. Critical control systems will be validated based on current GAMP guidance. All systems will be subject to Good Engineering Practice.

This strategy is consistent with the approach used at the Lenexa facility during their recent upgrade.

Details pertaining to the PQ of critical systems are outlined below.

Process Validation

The process validation strategy for the Irvine facility is a matrix based approach consistent to that of the Lenexa site and designed to comprehensively support the increased level of flexibility required for the facility. A matrix which brackets batch volume and representative media in each production line has been developed as the basis for validation. Successful process validation of these products will be referenced to support all products planned for transfer from the Lenexa to Irvine site. A minimum of three batches will be produced on each of the two production lines (Line 1 and Line 2) to demonstrate consistency and reproducibility.

  1. Scale: Validation of multiple media manufactured across a variety of production scale including minimum and maximum lot sizes (25 – 6000kg). A minimum of three lots will be produced on each manufacturing line to demonstrate consistency and reproducibility.

    It should be noted that Line 2 pre and post blenders can be operated with one of three IBC sizes (200L, 1000L, and 2100L). Four blender combinations have been selected for manufacture, each will be validated at maximum and minimum lot size resulting in 8 PQ batches, refer chart 1.

  2. Product Manufacturing Categories: The process validation will be carried out using a bracketing strategy with products having a known manufacturing history and considered representative of a worst-case manufacturing scenario for each group. The SAFC Cell Sciences & Development (CSD) team performed a technical assessment which included (but was not limited to) formulation type, raw materials interactions and milling characteristics. Multiple products were selected to represent one of three major media manufacturing categories:

    a. Classical

    b. Complex Chemically-defined

    c. Complex Protein-containing

  3. Analytical Assessment: Each lot will be assessed for the following:

    a. Finished Product Specifications

    b. Growth promotion

    c. Product homogeneity (Refer to Table 2)

    d. Particle Size Analysis

Table 1. Process Challenges by Media Category

Media Category Specific Process Challenges Number of Lots
Classical • Raw material interaction presenting milling challenge (RM)
• Low melting point raw materials presenting milling challenge (MP)
• Growth promotion test as measure of manufacturing success (GP)
3
Complex Chemically-defined • Chemically defined (CD)
• Raw material interaction presenting milling challenge (RM)
• Complex formulation subgroups providing additional manufacturing challenge (CF)
• Low melting point raw materials presenting milling challenge (MP)
6
Complex Recombinant Protein-containing • Protein-containing (PC) and chemically defined (CD)
• Complex formulation subgroups providing additional manufacturing challenge (CF)
• Low melting point raw materials presenting milling challenge (MP)
• Growth promotion test as measure of manufacturing success (GP)
2

A total of 11 manufacturing lots using five media formulations representing specific process challenges (refer to Chart 1) will be produced to assess the manufacturing process challenges as described above.

Chart 1. Validation Runs per Product Manufacturing Category

Table 2. Acceptance Criteria for Process Validation

Homogeneity Testing Acceptance Criteria
Amino Acids < 10% RSD
Vitamins < 10% RSD
Trace Metals < 15% RSD
Finished Product Specification Pass
Particle Size Analysis For Information Only; To be reviewed for alignment with Lenexa d90 guidelines

Processes will be controlled and validated based on critical process parameters identified during system impact assessments and defined during engineering studies. Where appropriate, these critical parameters for pre-blending, milling and post-blending will be harmonised between Irvine and Lenexa. For example equivalent milling speed and product temperature specifications are likely to be applied. However, blending times will be optimised based on equipment design at the Irvine facility.

Following post-blending of the batch, representative samples will be taken throughout the packaging operation at specified intervals. A detailed sample plan will be prepared in advance of PQ with a scientific rationale to justify sample and test requirements. Product homogeneity will be evaluated by quantitative analysis of selected raw materials including amino acids, vitamins and trace metals. In addition, samples will be tested against established finished product acceptance criteria, including growth promotion testing, where applicable. Pre-determined acceptance criteria will be harmonized with those applied at Lenexa (Refer Table 2). Non-compendial test methods will be validated prior to the PQ program and all internal test methods will be harmonized with Lenexa.

In-process hold times will be qualified to support routine production; this will be built into the sample plan.

Case Study

Following the successful completion of the above Performance Qualification, a Case Study will be conducted to demonstrate the practical comparability between the Lenexa, Kansas and Irvine, Scotland dry powder media manufacturing sites. The case study will include the following:

  1. Assessment of Chemical Composition

    • Amino Acids

    • Vitamins

    • Trace Metals

  2. Cell Culture Growth & Viability

  3. Finished Product Specifications

  4. Particle Size Analysis

Cleaning Validation

The cleaning validation strategy proposed for the DPM facility at Irvine is consistent with the approach used previously for cleaning validation at the SAFC Lenexa site.

Equipment cleaning processes will be controlled and validated based on the critical parameters of Temperature, Action, Concentration and Time (TACT) and the associated Standard Operating Procedures.

Where appropriate, these critical cleaning parameters will be harmonised between Irvine and Lenexa. For example equivalent cleaning agents and concentrations are likely to be used. However, temperature and time will be optimised based on equipment design and engineering runs at Irvine.

A risk assessment has been carried out by the Lenexa CSD team to identify representative products for the cleaning validation exercise. This assessment took into account the contamination risk to follow-on batches based on raw material solubility, concentration, production history at the Lenexa facility and ease of detection.

In conclusion a batch matrix which brackets batch volume and representative media in each production line has been developed and will be used as a basis for validation (Refer Table 3). Validation of all automated and manual cleaning processes will include triplicate runs to demonstrate consistent and repeatable cleaning across all batch sizes.

Table 3: Cleaning Validation Batch Matrix

  Lot Size
Media Category Product Cleaning Challenge
Line 1 CIP Min
Mid
Max
Complex Protein-containing
Complex Chemically-defined
Complex Chemically-defined
24365C
Media 1
Media 2
MP, SOL, REP, PC
CF, MP, SOL, REP
CF, MP, REP, RM
Line 2 CIP Min
Mid
Max
Complex Chemically-defined
Complex Chemically-defined
Complex Chemically-defined
Media 1
Media 1
Media 2
CF, MP, SOL, REP
CF, MP, SOL, REP
CF, MP, REP, RM
200L IBC Cleaning Validation Min
Mid
Max
Complex Chemically-defined
Classical
Classical
Media 1
R0274
D3187
CF, MP, SOL, REP
RM, MP, REP
REP
1000L IBC Cleaning Validation Min
Mid
Max
Complex Chemically-defined
Complex Protein-containing
Complex Chemically-defined
Media 2
24365C
Media 1
CF, MP, REP, RM
MP, SOL, REP, PC
CF, MP, SOL, REP
2100L IBC Cleaning Validation Min
Mid
Max
Classical
Complex Protein-containing
Complex Chemically-defined
R0274
24365C
Media 2
RM, MP, REP
MP, SOL, REP, PC
CF, MP, REP, RM
Key: CF   Cleaning of complex subgroups, e.g. oils
MP  Low melting point RMs potential for residue adherence
SOL Poor solublity RMs presenting cleaning challenge
REP  Media representative of major classification
PC    Protein content poses cleaning challenge
RM   RM interaction potential poses cleaning challenge

Sample requirements and predetermined acceptance criteria for cleanliness will be harmonised with those applied at Lenexa (Refer Table 4). All testing will be carried out using validated test methods. Successful cleaning validation data based on this strategy, comprising passing test results and verified critical process parameters, will be considered representative of all products to be transferred to the Irvine facility from Lenexa.

Table 4: Cleaning Validation Acceptance Criteria

Test Purpose Sample Location Acceptance Criteria
TOC To demonstrate removal of organic residues to acceptable levels Final Rinse TBD
Appearance To demonstrate removal of visible product residues Visible internal surfaces Visually Clean
Conductivity To demonstrate removal of cleaning agents and inorganic residues to acceptable levels Final Rinse ≤3uS/cm
Bioburden To demonstrate reduction to acceptable levels Final Rinse ≤100 cfu/mL
Endotoxin To demonstrate reduction to acceptable levels Final Rinse ≤0.25 EU/mL

Clean and dirty hold times will be defined and validated during this exercise to support routine production.

Critical Utilities

The following critical utilities will be installed to support the new facility. These will be specified, designed and qualified in accordance with the principles outlined in recognized industry guidance documents, for example the ISPE baseline guides. All critical utilities will be subject to extended PQ testing over a 1 year period to verify performance and consistency during routine operation. Regular reviews will be carried out during this qualification phase and on completion approved routine test plans will be implemented.

  • Purified water, tested to EP and USP monographs
  • Clean compressed air
  • Clean nitrogen
  • HVAC

Room Classifications and Environmental Conditions

All DPM manufacturing will be carried out in areas designed to Grade D specification; elevated air changes have been implemented in rooms where open powder will be exposed. The room classification strategy has been harmonized with the Lenexa facility and is deemed equivalent in all processing areas.

As a minimum the following parameters will be continuously monitored via a validated facility monitoring system:

  • Humidity in all areas where product is exposed
  • Temperature in all areas where Raw Materials or Finished Products are stored
  • Pressure differentials for all classified process areas and interlocks

The location of continuous monitoring probes will be based on risk assessment and/or temperature mapping data acquired during PQ.

A failure mode and effect analysis will be carried out to determine high risk areas for sampling throughout the DPM facility for viable testing. Based on this assessment, and current practice at Lenexa, an environmental monitoring program will be implemented. As a minimum this will involve weekly monitoring of air and surface samples for viable organisms.

Ongoing Compliance

Validation status of the DPM facility will be maintained through the effective implementation of standard operating procedures, maintenance and calibration programs, site change control, new product evaluation and transfer assessments, management review and a comprehensive routine validation schedule.

Routine validation requirements will be defined based on the results of the Irvine PQ studies, corporate guidance and harmonisation with the routine validation plans in place at the Lenexa facility.

Contingency Planning

This project is being supported by the staff and experience of the SAFC Lenexa site. Both facilities have applied similar design principles and validation strategies, as detailed within this document. The products selected for PQ studies at Irvine have been included in successful qualification activities at the Lenexa facility. The use of equivalent products, and the application of the same acceptance criteria, will clearly produce comparable data between the two facilities. This method of implementation ensures that harmonised and equivalent products will be provided from both the SAFC Lenexa and Irvine facilities providing a validated back-up facility if required.

Raw material specifications, finished product specifications, certificates of analysis and test methods will be harmonized between Lenexa and Irvine to ensure equivalency.

Further Information

SAFC intends to design and validate the Irvine Dry Powder Media facility to allow maximum flexibility and to meet our customer needs. If you have any questions or feedback on this white paper proposal please contact your SAFC representative.

On completion, the new DPM Facility will be available to audit on request.

Abbreviations

ACF Animal component free, CFR Code of Federal Regulations, CIP Clean In Place, COP Clean out of Place, CSD Cell Sciences Development, DPM Dry Powder Media, EP European Pharmacopoeia, FAT Factory Acceptance Testing, FDA Food and Drugs Administration, FMS Facility monitoring System, GAMP Good Automated Manufacturing Practice, cGMP current Good Manufacturing Practice, HVAC Heating, Ventilation, Air Conditioning, IBC Intermediate Bulk Container, IQ Installation Qualification, ISPE International Society for Pharmaceutical Engineering, MAC Maximum Allowable Carryover, MP Melting Point, OQ Operational Qualification, PQ Performance Qualification, PW Purified Water, RM Raw Materials, RSD Relative Standard Deviation, SAT Site Acceptance Testing, USP United States Pharmacopoeia, VMP Validation Master Plan

Contributors

Eleanor Mackinven, Production Supervisor (Irvine); Erik Klahn, Manager Technical Transfer/Packaging Solutions; Fiona Oldfield, Site Director (Irvine); George Wilson, Validation Engineer (Irvine); Jane Findlay, Quality Director SAFC EU Operations; Jeri Tumulty, Quality Manager (Lenexa); Jim McClung, Quality Engineering and Validation Manager; John Gibson, Operations Manager (Irvine); John Hampton, Development Supervisor (Lenexa); John Owings, Validation Engineer (Lenexa); Kurt Sundgren, Process Engineer (Lenexa); Raymond Lonergan, DPM Facility Project Manager (Irvine); Shay Sloan, Process Engineer (Lenexa), Simone Cassie, Validation Supervisor & Author (Irvine); Deb Stutz, Market Segment Manager

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