Pharma&Biotech

Andrew Harris / Lonza Biologics Inc., Portsmouth, NH 03801 / 16 September 2014© Lonza

CIP of Buffer Preparation “Rings”

Annual CIP Summit 2014

Pharma&Biotech

2Sep-14

Outline

Lonza

What are Buffer Preparation “Rings” ?

Supply Chain

Impact

ClP Buffer Ring CIP version 1.0 Buffer Ring CIP version 2.0

Next Steps

3Sep-14

Lonza

Lonza is a leading custom manufacturer of active pharmaceutical ingredients, intermediates and biotechnology solutions on the basis of advanced chemical synthesis, microbial fermentation and mammalian cell culture, which it supplies to the life sciences industry.

Headquartered in Basel,Switzerland.

40 major production and R&D Facilities worldwideemploying approximately 10,000.

4Sep-14

Lonza Biologics - Portsmouth

Located at the Pease International Tradeport in Portsmouth, NH

Contract Manufacturing Organization Custom manufacturer of therapeutic monoclonal antibodies and

recombinant proteins using mammalian cell culture

Licensed multi-product facility Clinical and Commercial 5k and 20k capacity

700+ employees - 24/7 operation

cGMP Manufacturing since 1996

5Sep-14

What are Buffer Prep “Rings?”

Form only at the Air-Liquid Interface (ALI), on the order of 0.5-3cm thick after a little as one buffer makeup

Slip Agents Used in bag manufacturing to reduce friction between film and equipment +

adjacent film Fatty acid amides: Most important slip agents for polyolefins (PE, PP, etc)

The raw materials are not ‘pure’ chemicals so have a molecular weight range

Anti-Block Agents Used in bag manufacturing to prevent wraps of a roll of film from sticking to each

other Inorganic – Talc (Magnesium Silicate), Silicon Dioxide, Calcium Carbonate

Polymers Likely impurities of buffer raw materials / salts Polyolefins (PE, PP), Fluoropolymers (PTFE), etc

Residual buffer materials / salts

6Sep-14

7Sep-14

Slip Agents

Hydrocarbons of various saturation with amide group. Most are mono-unsaturated

Slip agents’ raw materials generally contain some amount of various other slip agents Difficult to identify specific slip agents on FTIR

NH2

O

NH2

O

Erucamide (13-cis-docosenamide)

Oleamide (9-cis-octadecenamide)

8Sep-14

Anti-Block agents

Combat friction and Van der Waals forces during film blowing & casting

Added directly to polymer resin, migrates to surface during film manufacturing. Anti-block components melt at much higher temperatures than the polymers

Slip-agent-free plastics still contain Anti-Block agents Upon reducing Slip Agent content,

additional Anti-Block is added

9Sep-14

Supply Chain

Lonza has contacted raw material suppliers (chemicals and bags) and identify which use slip agents in their bag liners

Questionnaire to suppliers Slip agent usage information 2 levels back in supply chain Request to work with us to remove slip agents from their process

Few stated no, citing L/E data Some who stated yes, later encountered resistance from their suppliers

Lonza pursuing reductions in slip agent-containing materials throughout the plant Some quick-wins by switch part #’s or suppliers, mostly long term

goals

10Sep-14

Impact

Solubility, filterability, L/E, and toxicology assessments have shown no impact to patient safety

Filtration studies performed by Lonza showed that slip agents will not pass through a sterile filter in buffers utilized at Lonza, with the exception of detergent-based buffers At-scale evidence supports this. Rings/residue have not been found in

equipment/vessels downstream of the post-buffer prep filtration at Lonza

Detergent buffers are commonly used for viral inactivation Requires detailed calculations on permissible daily exposure (PDE) to justify

no impact to patient safety

11Sep-14

CIP

How do the bag & slip agent manufacturers clean their own equipment? Solvents! Ethanol, IPA, solvents with grit

Volatile Flammable Manual wipe-down Not translatable to CIP of

biopharmaceutical manufacturing equipment

Concentrated detergents Translatable to CIP

Key is dissolving hydrophobic residue in aqueous solutions

12Sep-14

Initial Plant Cleaning Philosophy

Previously validated CIP for Buffer Prep vessels WFI-only at 80-85 C ~30-45 minutes contact

Legacy rings required mechanical restoration of the vessels surfaces

“Enhanced Visual Inspection” by maintenance technicians proceduralized temporarily. Lonza utilized fluorescent droplight inspection from manway (200 lux)

Typical full chemical CIP of CIP100/CIP200 was not 100% successful in one area of the plant Exaggerated concentrations of CIP100/CIP200 were also not 100%

successful CIP150 was also not successful

13Sep-14

Buffer Ring CIP “version 1.0”

ProKlenz Booster (PKB) - Successful Hydrogen Peroxide + unique surfactant blend

14Sep-14

Buffer Ring CIP “version 1.0”

First validated use of ProKlenz Booster at Lonza Portsmouth

Low alarm limit for wash conductivity chosen as 9.5 mS/cm This is a 1.0%+1.0% solution, and was the manufacturer’s

recommended concentration to use

High alarm limit for wash conductivity chosen as 20.0 mS/cm This is a 2.5%+2.5% solution Manufacturer recommended not exceeding 3%, as 3% can lead to

SS surface oxidation “tinting” with long term use. Conservative approach to tank surface maintenance

0.5% safety factor from the 3% Acid wash with each CIP Annual acid wash PM CIP’s (more aggressive) on Buffer Prep tanks

15Sep-14

Buffer Ring CIP “version 1.0”

ProKlenz Booster is not a drop in replacement for skids/automation design for addition of one chemical per wash Not ideal to pre-mix CIP100 with ProKlenz Booster due to stability of

peroxide at high pH (requires frequent turnover of skid day tank)

ProKlenz Booster must be added after solution heat-up has occurred Due to the high foaming potential of ProKlenz Booster at temperatures

below 50°C Foaming reduces the effectiveness of the CIP

Peroxide would break down during heat-up This maximizes concentration of peroxide while in solution with

CIP100, as it is designed to work. Cleaning is designed to work with both chemicals together

Both CIP 100 and ProKlenz Booster added via totalized mass, to mass set point

16Sep-14

Buffer Ring CIP “version 1.0”

Detectability considerations

17Sep-14

Buffer Ring CIP “version 1.0”

Continuous Monitoring & Validation Both CIP100 and ProKlenz Booster added by mass,

monitored/alarmed by conductivity CIP100 is the primary contributor to the conductivity (and pH),

confirmation of the concentration of ProKlenz Booster is inferred from the success of the CIP100 confirmation (which occurs just prior) and the continuous monitoring scheme of the CIP.

18Sep-14

Buffer Ring CIP “version 1.0”

Pros Lonza Portsmouth has been successful in the removal of slip

agents from the buffer prep vessels post-CIP since implementation of this CIP

Cons Some surface oxidation “tinting” observed on equipment surfaces Visible rings post-CIP still occur occasionally (infrequent)

Slip agents not present in these rings, comprised of inorganic Anti-Blockagents and Polymers. Generally all hydrophobic inorganics

These post-CIP rings are remediated manually Wipes wetted with ambient solution of 5% CIP100 + 5% ProKlenz

Booster “Enhanced Visual Inspection” by manufacturing personnel in place as a

result

19Sep-14

Buffer Ring CIP “version 2.0”

Lonza has an ongoing initiative to develop an alternative to the currently validated peroxide-based CIP with ProKlenz Booster

Drivers / Goals1. Obtain 100% cleaning success2. Utilizing cleaning agents that do not impact the equipment surface

Phase 1 - Coupon-scale experiment to determine which variables are the most impactful, comparing rate of removal of residue Cleaning Agent Temperature Concentration

Utilized Engineering Firm with cleaning lab

20Sep-14

Buffer Ring CIP “version 2.0”Phase 1

Chemicals chosen: CIP100 + ProKlenz Booster

Baseline required for direct comparison CIP100 + CIP Additive

CIP Additive = non-ionic surfactant blend only Cosa CIP 95

NaOH-based + surfactant blend

Three Surrogate residues

21Sep-14

Buffer Ring CIP “version 2.0”Phase 1 Surrogate Soil

Developed surrogate residue based on historical residue identifications pre and post-CIP Pre-CIP rings – The actual residue being cleaned Blend of most common slip agents and inorganic anti-blocks / polymers

Oleamide, Erucamide, Stearamide – Talc / Polyethylene

Surrogate characteristics: White in appearance Fails water break test Resistant to cleaning:

Water @ 60C 1% CIP100 @ 60C for 20 minutes Dry wipe / manual

Dissolves in cleaning solution instead of coming off in chunks Can be reproducibly generated and soiled onto coupon Adheres in sufficient quantity to facilitate gravimetric analysis

22Sep-14

Buffer Ring CIP “version 2.0”Phase 1 Surrogate Soil

Oleamide and Erucamide Stearamide Surrogate could not be made

that met all criteria

Surrogate formulation Slip agent dissolved in a solvent plus

small percentage of solids (talc/PE), prepared and spiked at elevated temperature

Air dry ambient until solvent is removed Heat treat in autoclave Bake in oven to dry condensate

Formation method far different than at-scale residue

Complete cleaning not required to make relative comparisons of rate of removal

23Sep-14

Emersion batch could not be used, as coupons would become re-soiled upon removal due to hydrophobic residue floating on the surface

Falling film device Control flow rate, temp Representative worst case of

cascade flow on vessel walls

Buffer Ring CIP “version 2.0”Phase 1 Apparatus

24Sep-14

Buffer Ring CIP “version 2.0”Phase 1 Results

25Sep-14

Buffer Ring CIP “version 2.0”Phase 1 Results

26Sep-14

Buffer Ring CIP “version 2.0”Phase 1 Results

Conclusions from Phase 1 coupon-scale cleaning of surrogate residue Temperature is impactful

80 C performs better than 60 C Chemical concentration is impactful, but not as much as

temperature 3% performs better than 1%

CIP 100 + CIP Additive outperforms both CIP 100 + ProKlenz Booster

High likelihood that CIP 100 + CIP Additive will perform as well or better than CIP 100 + ProKlenz Booster

27Sep-14

Next Steps

Supply Chain: Continue to put pressure on suppliers to remove slip agents from

materials/processes.

Continue CIP development Phase 2 - Complete final coupon-scale experiments with residue

generated in same manner as at-scale residue Optional Phase - Evaluate additional parameters Phase 3 - At-scale trials in ad hoc buffer preparations

28Sep-14

Thank You!