Continuous Manufacturing of Drug Substancesª Apresentação_John Cyganowski... · Drug Substances....

John Cyganowski, Director Manufacturing Sciences & Technologies,

Downstream Americas, Merck

Presented to:

VIII SYMPOSIUM ANVISA, IPS/FIP and SINDUSFARMA:– NEW

PHARMACEUTICAL FRONTIERS June 2019

and Emerging Regulatory Guidance

Continuous Manufacturing of Drug Substances

Objective

Provide useful general comments & approaches

1This seminar provides general guidelines but each molecule is unique and requires its own assessment

2 Discussion limited to a few major concerns

3This is an evolving area- new data, technologies, and analysis may cause shifts in risks, priorities, and best practices

Continuous Manufacturing of Drug Substances| 17 June 20192

Agenda

1

6

5

4

2

3

Background

What are Next Gen technologies?

PD/QbD- Process changes

- Implications- Risk Identification

Risk Identification

- New technology- Top level risks

Lot Management

- Regulatory definition

- Implementation

- Manufacturing planning

Conclusions- Summary

- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7

Regulatory Environment

- ICH Q-13- FDA/EMA Guidance

Background

Next Generation Processing Technologies

Bioreactor Clarification Affinity Chromatography

Virus Inactivation

Purification Chromatography

Polishing Chromatography

Viral Clearance

Concentration & Diafiltration

Today (> 2017): Standard mAb process template

Banking, Seed-train Inoculation

Perfusion in production or n-1 bioreactors with cell recycling

Linked to DSP

Single-use assemblies

Cycling adsorbers

Continuous virus inactivation

SPTFF concentration

Linked upstream & downstream


Flow through adsorbers

Cycling adsorbers

SPTFF concentration

Linked operations


SPTFF concentration

Continuous DF


Tomorrow (2018–2020+): Next Generation mAb Processing with process intensificationPerfusion Capture & Inactivation CEX & IEX & Removal

Intensified seed train with perfusion production

Continuous Capture & In-line virus inactivation

Connected flow through polishing

Concentration & Diafiltration

Continuous concentration/DF

Title of Presentation | DD.MM.YYYY4

Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7


– ICH Q-13– FDA/EMA Guidance

PD/QbD for mAb Manufacturing

Process Step Step Quality Attributes Step Process Attributes Process Changes

Bioreactor HMW, Acidic Variants,

Galactosylation,

Afucosylation, HCP, DNA

Titer, cell density,

viability, cycle time

Fed-batch ➔ perfusion at n, n-1

Harvest Disulfides Centrifuge/filters ➔ flocculation, cell retention

devicesPrA Capture HCP, HMW Yield Faster cycling, membranes

Low pH VI Virus LRV, HMW Yield Batch ➔ inline

Purification HMW, Acidic Variants, HCP Yield, pool volume CEX bind-elute ➔ flow through, membranes

Polish HCP, virus LRV, DNA Yield AEX flow through ➔ carbon, AEX membrane

Virus

filtration

Virus LRV Yield Extended operation, constant flow

UFDF HMW, concentration, buffer Yield Batch ➔ continuous SPTFF & CDF

Sterilization Sterility Constant flow

Integration Linked (bulk ➔ surge tanks), single-use

closed systems

Adapted from AMAB Case Study, CMC 2009

6 Continuous Manufacturing of Drug Substances| 17 June 2019

Move target

operating point

(shorter residence

times, longer

processes, higher

loading, higher

concentrations)

Operation may be

cyclic with

variable feed.

Move location to

match operating

point

Size based on

capabilities (start

wide & narrow

with experience)

Thorough

analysis of failure

modes with

increased

sensors &

analysis to detect

variation &

automation to

respond quickly

State of control

is not steady-

state

Mostly the same

FMEA type

analyses except

flocculation

clarification

Greater focus on

disturbance

generation &

propagation, and

traceability.

Process linkage

requires residence

time distribution

analysis.

Similar since same

base technologies

(except flocculation

& perfusion)

Change in VF & SF

hydraulics from

constant pressure

to constant flow

with pressure limit

Linking operations

ties steps together

with ~same mass

flow throughout

PD/QbD

Implications for PD & QbD

Same at high

level since

patients and

overall plant

metrics are the

same

More focus on

process attributes

of reliability, lot

carryover, and

raw material

sensitivity

Quality & process attributes

Process parameters

Risk assessments

Operating point

Design spaceControl strategies

7


Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7


- ICH Q-13- FDA/EMA Guidance

Risk Identification

New technology/process change

Limited experience with Continuous Processing

Emotional reaction

Rational reaction

Many unknowns

Assume worst case

• Out of comfort zone, Fight or Flight reaction

Manage

• Standard industry manufacturing evolution

• Gain experience & learn to reduce risk

• New technologies (SU) reduce risk

• Potential opportunity in change

• Managing adoption & implementation

• Risk/benefit assessment

• Gap identification


EU EMA

Innovation Task Force

Mihokovic ICBIII Portugal 2017

Risk Identification

Top level perceived risks

Regulatory Filing

• Current widespread WW NGP support by health

authorities on grounds of quality, flexibility, availability,

agility, and cost (Woodcock 2015, Mihokovic 2017)

• In house regulatory departments most conservative

• Regulatory questions on maintaining quality

• Through process perturbations

• Bioburden management sampling, detection, correction

• Use of automation & training in control strategy

• Meeting (FDA type C) with health authorities on

strategy (pre IND filing) strongly recommended - new TT,

ITF, IMT offices for emerging technologies

• “consensus that continuous manufacturing can be

effectively executed within the existing regulatory

framework, and there are no major regulatory hurdles

for manufacturers to implement continuous

manufacturing.” (Nasr 2017)

https://www.ema.europa.eu/en/documents/presentation/presentation-innovation-task-force-itf-dr-marisa-papaluca-amati_en.pdf

[email protected]

Brorson, ICBII Berkeley 2015

US FDA CDER

Biotechnology Manufacture

Emerging Technology

Japan PMDA

Innovative Manufacturing Technology Working Group

Nasr 2017


Risk Identification


Quality Attributes

Observed improved product quality

• Labile orphan drugs require perfusion residence time,

perfusion more consistent

• Reduced tanks/shorter DSP times limit degradation

• Shorter inline low pH virus inactivation times reduce

degradation

Observed lower bioburden (Mozzachio 2017)

• Gamma irradiated single use more reliable

• Closed system implementation

Extractables & leachables levels lower

• Perfusion flush out - lower cell impact

• Efficient downstream clearance (Naratajan 2012)

US FDA OPQ CDER

Regulatory Updates

Alicia Mozzachio

PDA Singapore 2017


Risk Identification


Process Attributes

• Very low overall rate of process failures

• High perceived concern over hundreds of component failure scenarios where product is potentially scrapped - a potentially very expensive outcome

• Need to manage risks: Identify in design & pilot phase, qualify equipment for reliability, sensor calibration, raw material consistency, build in and test automation response since manual response not timely enough, single-use installation training & integrity testing

• Many indicate a continuous process is easier to run than a batch process

• Potential for higher yields (smaller systems, fewer tanks)

• Limited public process information sharing - new collaborative structures (MIT CAACB, NIIMBL, BPOG) may enhance


Risk Identification


Achieving Benefit Targets Hall 2017• More flexible (quicker to configure and

scale, improved response to demand variability, configurable for a broad variety of proteins, facility mobility, right sized production with forecast uncertainty)

• Faster deployment (rapid facility build with capacity expansion & tech transfers, speed to market, reduced validation, reduced changeover time for SU)

• More economical (lower $/g, lower Capex & tech transfer, lower $/g with increasing titers, allowing more deferment of investment, facilitating increased market share because first in molecule class)

• More reliable (lower bioburden, more consistency, more automation/less labor)

BPOG 2017• More flexible (modular operations

easy to configure for each molecule, buffer on demand, output flexible with time, closed system requires less environmental control)

• Reduced footprint (higher productivity, less tanks, facilitates closed systems)

• Reduced capital spend (higher productivity, single use replaces stainless, facilitates better bioburden mgmt., reduced environmental control)

• Better resource utilization (longer operation to reduce sizing, single use to reduce set up/turnaround)


Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7



Lot Management

Code of Federal RegulationsTitle 21 - Food and Drugs, Volume: 4

Date: 2018-04-01Original Date: 2018-04-01Title: Section Â§ 210.3 - Definitions.Context: Title 21 - Food and Drugs. CHAPTER I - FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF

HEALTH AND HUMAN SERVICES (CONTINUED). SUBCHAPTER C - DRUGS: GENERAL. PART 210 -CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR

HOLDING OF DRUGS; GENERAL. § 210.3 Definitions. (2) Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.(10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits[43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar. 3, 1986; 58 FR 41353, Aug. 3, 1993; 73 FR 51931, Sept. 8, 2008; 74 FR 65431, Dec. 10, 2009]

Japan Ministry of Health, Labor and Welfare, Ministerial Ordinance No. 179 2004

“Lot” throughout this Ministerial Ordinance means a grouping of the products or raw materials that are manufactured so as to have a uniform quality in a series of the manufacturing process for a certain manufacturing period.”


Lot Management

Definitions

Identified amount

• Segregated - Lot is distributed across the entire process train, want limited

mixing/carryover between lots just as with batch

Uniform character & within quality specifications

• Use final mixed pools (DF or post UFDF sample) mimic batch operation

• Sample & assay final mixed pool

Intermediates within quality limits

• Consider integrated load to entire batch, not each momentary fluid element

• Sampling rate - must catch significant deviations to lot pool quality

• Split stream - cumulative sample to represent batch average


Lot Management

Manufacturing planning: sizing and frequency

Market demand (kg mass) - driven mainly by annual or planning period demand (patients, clinical, inventory build)

Manufacturing campaigns (weeks/months) - driven mainly by demand, existing capacity for multiuse or single product, risk & cost (plant utilization)

# Lots per campaign (days) - driven by balance of release test costs vs expected failure cost

Lot based on volume or time prefer volume to keep uniform Protein A loading & more uniform DSP

1

2

3

4

5Cycles per lot driven by unit operation costs

Example: Size plant for 1 batch

Large facility

High capital cost

Lower testing costs

Long downtime

Poor plant utilization

High overhead costs

Short manufacturing time

Reduced labor cost

High risk


Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7



Disclaimer

I do not represent or speak for the ICH. My comments are those of an industry based observer.

ICH Mission

• ICH's mission is to achieve greater harmonization worldwide to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.

• Established in 1990. Driven by the rise of global pharmaceutical development (and later manufacturing). Provide a consensus between different and sometimes conflicting regulatory schemes.

Topics

• Quality Guidelines

• Safety Guidelines

• Efficacy Guidelines

• Multidisciplinary Guidelines

International Committee for Harmonization (ICH)


ICH Q13 Status

• The guidance publish date is November 2021

• Public comment date is June 2020

• 4 Documents – Concept Paper, Business Plan, Work Plan and Experts list

Objectives of ICH Q13

• Harmonize CM-related definitions

• Articulate key scientific approaches for CM (continuous manufacturing)

• Harmonize regulatory concepts and expectations for CM across the regions

ICH Q13: Continuous Manufacturing for Drug Substances and Drug Products - Overview


40614_JPG_by_ClipartOfcom

Definitions and regulatory concepts require further explanation in the regulatory context

• Continuous manufacturing

• Startup/shutdown

• State of control

• Process validation

• Continuous process verification

Key scientific approaches for CM

• System dynamics

• Monitoring frequency

• Detection and removal of non-conforming material

• Material traceability

• Process models, and advanced process controls.

ICH Q13: Continuous Manufacturing for Drug Substances and Drug Products - Topics


Facilitates consistent science-and risk-based implementation and regulatory assessment of CM across different regions

CM-related regulatory expectations

• Harmonized expectations for dossier approval

• Lifecycle management

• Marketing Applications

• Post Approval Changes

• Site Implementation

• Quality Systems

Have publicly said that they are in favor

Feel it will result in safer, more accessible drugs

BUT

Official guidance is slow in coming

Regulatory Environment – What does the FDA have to Say?


This guidance provides information regarding FDA’s current thinking on the quality considerations

for continuous manufacturing of small molecule, solid oral drug products that are regulated by

the Center for Drug Evaluation and Research (CDER). The guidance describes several key quality

considerations and provides recommendations for how applicants should address these

considerations in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and

supplemental NDAs and ANDAs, for small molecule, solid oral drug products that are produced

via a continuous manufacturing process. FDA supports the development and implementation of

continuous manufacturing for drug substances and all finished dosage forms where appropriate,

including those submitted in NDAs, ANDAs, drug master files (DMFs), biologics license

applications (BLAs), and nonapplication over-the-counter (OTC) products. Scientific principles

described in this guidance may also be applicable to continuous manufacturing technologies used

for these drugs. However, this guidance is not intended to provide recommendations specific to

continuous manufacturing technologies used for biological products under a BLA.

FDA & EMA have proposed meetings/forums to discuss the implementation of “Innovative Technologies”.

FDA & EMA

What support do these Regulators have for CM ?


FDA

• Emerging Technology Program (ETP) advocates for innovative technology while balancing risk vs. benefit.

Scope

1. Product technology

2. Manufacturing process

3. Control strategy

Objective

• Encourage development of emerging technology lead to pharmaceutical innovation and modernization.

• https://www.fda.gov/about-fda/center-drug-evaluation-and-research/emerging-technology-program

EMA

• Innovation Task Force (ITF) A forum for early dialogue to identify scientific, legal and regulatory issues of emerging therapies and technologies

Scope

1. New delivery system

2. New manufacturing technology

3. Novel statistical approach (e.g. modelling & simulation) – etcetera

Objective

• EMA to help clarify questions regarding the road to market of innovative medicines

• https://www.ema.europa.eu/en/human-regulatory/research-development/innovation-medicines

https://www.fda.gov/about-fda/center-drug-evaluation-and-research/emerging-technology-program

https://www.ema.europa.eu/en/human-regulatory/research-development/innovation-medicines

Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Viral Safety

- SPQ - Polishing


7



Viral Safety

General Considerations

• Perfusion harvest RVLP load vs fed-batch

• Perfusion contamination likelihood with higher media volumes

• Perfusion facility segregation with closed processes

Validation challenges

• Cyclic operation may increase pauses

• Mass balances for cyclic operations

• Extended operation of virus filters over days

• Higher loadings and concentrations

• Use of inline spiking


Viral Safety

Customer Application: Inline SPTFF with Eshmuno® Q resin

Protein solution

Water

Equilibration buffer

Sanitization buffer

Concentrated, purified proteinwaste

A

0.3 m2 total SPTFF membrane area

10 mL CV per Eshmuno® Q column

Bioprocessor benefits

• Up to 5x higher HCP clearance

• 4x loading & 5x productivity increase

• Maintain robust virus clearance

• Run in batch and continuous modeElich, ACS San Francisco 2016


Viral Safety

Intensified AEX flow through: pre-concentration & high loading

0

5

10

15

20

25

30

35

0 100 200 300 400 500 600 700 800

Cum

ula

tive H

CP in P

ool (P

PM

)

mAb loading (mg/mL resin)

HCP Breakthrough

11 mg/mL

32 mg/mL

46 mg/mL

82 mg/mL

99 mg/mL

MAb feed conc.

0

1

2

3

4

5

6

0 20 40 60 80 100 120

Impro

vem

ent

facto

r above

non-S

PTFF f

eed

mAb feed concentration (mg/mL)

Improvement vs. mAb feed concentration10 ppm HCP endpoint

Mass Loading (g/L resin) Productivity (g/L resin/hr)

• Eshmuno® Q resin at 200 µL RoboColumn® scale

• 3.8 minute residence time. pH 8.4, 5.5 mS/cm load

tcycle: same non-load times for all conditions

▪ 4x increase in mass loading with SPTFF pre-concentration

• Reduced loading at high feed concentrations, possibly due to mAb-HCP interactions

▪ Increase productivity in 2 ways: boost mass loading, decrease cycle time

▪ Optimal Eshmuno® Q resin feed concentration for mAb A: 80 g/LContinuous Manufacturing of Drug Substances| 17 June 2019

27

Viral Safety

Polishing AEX flow through adsorption: Eshmuno® Q resin

0

1

2

3

4

5

6

0 200 400 600

MV

M L

RV

Loading (g mAb/L resin)

11 g/L

79 g/L

0

1

2

3

4

5

6

0 200 400 600

XM

uLV

LR

V

Loading (g mAb/L resin)

11 g/L

79 g/L

mAb1: pI 8.1-8.4, 125 ppm HCP, pH 8.4, conductivity ~5.1 mS/cm

MVM: 2 x 106 TCID50/mL, XMuLV: 1 x 106 TCID50/mL

Column volume: 1 mL (dia = 0.8 cm, h = 2 cm)

Residence time: 2 min (traditional) or 8 min (batch)

Higher concentrations & loading, shorter residence timeContinuous Manufacturing of Drug Substances| 17 June 2019

28

Viral Safety

Polishing AEX flow through adsorption: Eshmuno® Q resin w pause

XMuLV

• Good XMuLV retention, but consistent virus breakthrough throughout the run ; LRVS ~3.0 logs.

• No impact of the flow interruption on XMuLV removal

MVM

• Effective MVM retention but slightly increased breakthrough with increased loading; LRVs >4.0 logs at 400 g/L

• No impact of the flow interruption on MVM removal

Co-spike, 1 mL column, 2 min residence time, pause at 300 g/L

®®


29

Viral Safety

Polishing by flow through adsorption

Chemistry: + charged quaternary amine ligand

• At pH 7 binds - charged viruses, DNA, HCP, not + mAbs

• Use of a tentacle or gel structure increases ligand density for added capacity and binding strength

Support matrix:

• Beads provide high internal surface area (hard to access) and strength at high pressure drop- long residence times, low productivity

• Membranes provide easy access to low surface area at low pressure drop-short residence time, moderate productivity

• Unique gel membrane supported on a polymer net provides easy access to high surface areas at low pressure drop- short residence times, high productivity

Devices: Packed resin columns and layered membrane modules

• Scalability, flow distribution, ease-of-use


Viral SafetyPolishing AEX flow through adsorption: NatriFlo® HD-Q Recon mini w pause

XMuLV: no impact of pause; LRV >5.0 logsMVM: no impact of pause; LRV >5.0 logs

Study #1: 0.2 mL module, 2 mL/min, co-spike, pause at 5 kg/L

®®


Viral SafetyPolishing AEX flow through adsorption: NatriFlo® HD-Q Recon mini w pause

XMuLV: no impact of pause; LRV >5.0 logsMVM: no impact of pause; LRV >5.0 logs

Study#2, Co-spike, 0.2 mL device, 1 mL/min, pause at 7.5 kg/L

®®


Agenda

1

6

5

4

2

3

Background




Risk Identification


Lot Management


- Implementation



- Acknowledgements

- References

Virus Safety

- SPQ - Polishing


7



Wrap-up

Summary

Next Generation Processing

• New technologies (flocculation, membrane adsorbers, single-use assemblies), operation

(perfusion, cycling, linking, pre-concentration) for higher productivity, speed, flexibility,

quality

• Adoption of Linked Unit Operations to manage risk

• Same lot definition- need segregation, lot sizing, cycles per lot

• Change in operating point (shorter residence times, higher concentrations & loading,

longer processes, pauses)

• Robust AEX, VF, and CVI processes may need inline spiking to validate

Big thanks to

• Herb Lutz, Brian Hubbard, Thomas Elich (SQPQ), David Bohonak (VF), Ushma Mehta

(virology), Elizabeth Goodrich, Mike Phillips, FDA


Wrap-up

References

• BPOG, Biopharm Operations Group, Technology Roadmap, biophorum.com, 2017

• Bisschops, Mark, M. Krishnan, “Continuous BioProcessing: Technology and Regulatory Challenges and Mitigation Strategies”, Conference, Oxford, UK, June 27, 2017

• CMC Biotech Working Group, A-Mab: A Case Study in Bioprocess Development, Emeryville, CA: CASS, 2009

• Elich, Thomas, E. Goodrich, H. Lutz, U. Mehta, “Linking single pass tangential flow filtration with anion exchange chromatography for intensified mAb processing”, ACS mtg. San Francisco, Apr. 2017

• FDA, “Submission of Quality Metrics Data: Revised Draft Guidance for Industry”, UCM455957, Nov. 2016, 21CFR 210.3(b)

• Gallagher, Parish, CTO Upstream, GE, ”Risks and Benefits of Concurrent Multi-Product Manufacturing”, CBI Conference, San Diego Dec 2017

• Gillespie, Chris, Melissa Holstein, Lori Mullin, Kristen Cotoni, Ronald Tuccelli, John Caulmare, Patricia Greenhalgh, Biotechnol. J., May 2018

• Geigert, J, “The Challenge of CMC Regulatory Compliance for Biopharmaceuticals”, Kluwer Academic/Plenum Publishers, NY, NY 2004

• Hall, Kimball, Sr. VP Roche, “Achieving Efficient Facilities: Thinking about our industry in a revolutionary new way”, CBI Conference, San Diego Dec 2017


https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM455957.pdf

Wrap-up

References

• ICH, Quality Risk Management, Q9, Nov 2005

• Johnson, Sarah A., M.R. Brown, S.C. Lute, K.A. Brorson, “Adapting Viral Safety Assurance Strategies to Continuous Processing of Biological Products”, Biotechnol. and Bioeng., 114, pp21-32, 2017

• Kaiser, Klaus, “Continuous or Isolated- not feasible without single-use”, CBI Conference, San Diego Dec 2017

• Lee, Wayne, M. Bisschops, M. Krishnan, “Continuous BioProcessing: Technology and Regulatory Challenges and Mitigation Strategies”, PDA Modern Biopharmaceutical Processing Conference, Singapore, Nov. 2017

• Lutz, H., W. Chang, T. Blandl, G. Ramsey, J. Parella, J. Fischer, E. Gefroh, “Qualification of a novel inline spiking method for virus filter validation”, Biotechnol. Prog., 27, pp 121-128, 2011

• Lutz, H, presentation to CDER OPB on continuous virus inactivation using low pH, 2017

• Mihokovic, Nino, “Continuous manufacturing- EMA perspective and experience”, ICBIII, Portugal 2017

• Natarajan, Venkatesh, E. Goodrich, F. Mann, “Using Single Use Technologies to Improve Speed to Clinic- A Case Study”, Recovery of Biologicals, 2012

• Sinclair, Andrew, “A Standardized Economic Cost Modeling Approach to Evaluating Facility & Process Innovation”, CBI Conference, San Diego, Dec 2017

• Widener, James, Executive Director PD, Amgen, ”Application of Frontier Science- Lessons from Implementation of Next Generation Manufacturing at Amgen’s Singapore Facility”, CBI Conference, San Diego Dec 2017


John Cyganowski

Email: [email protected]

Contact

Thank you

Any Questions?

Merck, the vibrant M, Eshmuno, NatriFlo, Natrix, and RoboColumn are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.

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Continuous Manufacturing of Drug Substancesª Apresentação_John Cyganowski... · Drug Substances....

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