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RAW MATERIAL MANAGEMENTRAW MATERIAL MANAGEMENT


BIOT 4801 Biotecnologa Operacional I

UIPR BarranquitasJA Negrn, Ph.D.


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ContentContent Raw material management

Quality

Raw materials in a biopharmaceutical environment

Types of materials

Introduction to regulation from FDA

Analytical tests for identity, quality, quantity, and contaminants

AAS, ICP

IR

HPLC

Microbiological

Endotoxins detection Water

Purified water

Water for injection


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QualityQuality Quality Assurance (QA)

It is the sum total of the organized

arrangements with the objective of ensuringthat products will be of the quality required

for their intended use.

Good Manufacturing Practices (GMP)

QA

GMP

Is that part of Quality Assurance aimed atensuring that products are consistently

manufactured to a quality appropriate to their

intended use.

Quality Control (QC) Is that part of GMP concerned with sampling,

specification & testing, documentation &

release procedures which ensure that the

necessary & relevant tests are performed &

the product is released for use only afterascertaining its quality.

QC


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Quality ControlQuality Control

A process employed to ensure a certain level

of quality in a product or service.

Analysis of raw materials

Analysis finished formulation


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Application of GMP Guidance to API ManufacturingApplication of GMP Guidance to API Manufacturing

http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm200364.htm#P208_6121


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Raw Materials in a Biopharmaceutical IndustryRaw Materials in a Biopharmaceutical Industry

Biological or chemical substances used to manufacture theproduct Chemical reagents

Organic, inorganic

Cell culture nutrients

Detergents Anti foam agents

Enzymes

Cleaning agents

Growth factors Chromatographic media

Other


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Management of MaterialsManagement of Materials

According to the U.S. Federal Drug

Administration FDA, there should be writtenprocedures describing the receipt,

, , , ,

sampling, testing, and approval or rejection of

materials.


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Department of Health and Human ServicesDepartment of Health and Human Services

U.S. Food and Drug AdministrationU.S. Food and Drug Administrationhttp://www.fda.gov/http://www.fda.gov/

Responsibility of FDA


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RAW MATERIAL MANAGEMENTRAW MATERIAL MANAGEMENT Guidance for IndustryGuidance for Industry

Q7A Good Manufacturing Practice (GMP) Guidance forQ7A Good Manufacturing Practice (GMP) Guidance forActive Pharmaceutical Ingredients (APIs)Active Pharmaceutical Ingredients (APIs)

Guidance regarding GMP for the manufacturing APIs

Operations of receipt of materialsreceipt of materials, productionproduction, packaginpackaging,repackagingrepackaging, labelinglabeling, relabelingrelabeling, quality controlquality control, releasrelease,

storagestorage and distributiondistribution of APIs and the related controls.

ttp: www. a.gov ICECI Comp anceManua s CompliancePolicyGuidanceManual/ucm200364.htm#P20

8_6121


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Raw Material Sampling and DispensingRaw Material Sampling and Dispensing

Sampling Sampling needs to be done in accordance with

approved written procedures, such as SOPsSOPs(standard operating procedure) in order to avoidand/or detect contamination.

Most of the samples need to be tested and

analyzed for microbial content against the specifiedlimits. So, one has to ensure that during samplingenvironmental microbes do not contaminate thesamples drawn.

Dispensing

Accuracy of weighing is very critical, as any of theweighing errors will affect the composition of finalproduct.


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Verification of Raw MaterialsVerification of Raw Materials Incoming raw material should not be used until it has been

inspected and verified as conforming to the specifiedrequirements.

This verification should be in accordance with therequirements of the quality plan or other documented

.

This verification should include a check that: the labels indicate that it is the item ordered

the containers are not damaged and all seals are intact

materials and packaging components received do correspond to

the items ordered there is no evidence of alteration and that the delivery generally

appears to be in good condition and suitable for use


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Sampling and Testing of IncomingSampling and Testing of IncomingProduction MaterialsProduction Materials At least one test to verify the identity of each

batch of material should be conducted Complete analyses should be conducted on at

least three batches before reducing in-house

testing. Supplier's certificate of analysis

Sometimes can be use in place of additional tests

Certain materials and in certain circumstances areexempted from analysis if manufacturer'scertificate of analysis is obtained.


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What may be required in a Certification of Analysis?What may be required in a Certification of Analysis?1. Name and Address of Certifying Body

2. Title of Document

3. Description of Material

4. Reference Material Code and Batch Number

5. Description of Certified Reference Material (CRM)

6. Intended Use

'

8. Hazardous Situation9. Level of Homogeneity

10. Certified Values and their Uncertainties

11. Traceability

12. Values Obtained by Individual Laboratories or Methods

13. Uncertified Values

14. Date of Certification

15. Period of Validity

16. Further Information

17. Names and Signatures of Certifying Officers


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Example of aExample of a

Certificate of AnalysisCertificate of Analysis

http://www.elannutrition.com/


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Raw Material AnalysisRaw Material Analysis Atomic Absorption

Spectroscopy (AAS) Infrared

Spectroscopy (IR) Portable Raman Spectrophotometer

HPLC Gravimetric analysis

Microbiological tests

Endotoxins analysis(LAL)

laser: 120mW 785 nm resolution: 8 cm-1

spectral range: 200 - 2000 cm-1

http://deltanu.com/inspector-raman/


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Essential trace elements -Fe, Cu, Zn, Cr, Se, Ca,

Mg, Co, Mo, I, Si, and Mn

Toxic elements -Cd, Mo, Pb, Hg, As, Sn,

ass e ementa mpur t es s, an g Class 2 elemental impurities are metal

catalysts, which include Cr, Cu, Iridium, Mn,

Mo, Ni, Os, Palladium, Pt, Rh, Ru, and Va.


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Atomic Absorption Spectroscopy (AAS)Atomic Absorption Spectroscopy (AAS) Atomic absorption spectrometers use light absorption to measure the

concentration of gas-phase atoms.

It is the most common method to analyze metals and metalloids.

Technologies

Flame atomic absorption spectroscopy (FAAS)

Graphite Furnace atomic absorption spectroscopy (GFAAS)

Inductively Coupled Plasma (ICP)

Elements detectable by atomic absorption are highlighted in pink in this

periodic table:


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Flame Atomic AbsorptionFlame Atomic Absorption

Spectroscopy (FAAS)Spectroscopy (FAAS)

Atomic Absorption is the process where vaporized atoms

absorbs light and is measured. During combustion, atoms of the element of interest in the

sample are reduced to free, unexcited ground state atoms,

.


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Graphite Furnace Atomic AbsorptionGraphite Furnace Atomic Absorption

Spectrometry (GFAAS)Spectrometry (GFAAS) Electrothermal atomisation

It requires a graphite furnacegraphite furnace, where after thermal pre-treatment the

sample is rapidly atomized. Graphite furnace atomic absorption spectrometry is a highly sensitive

spectroscopic technique that provides excellent detection limits formeasuring concentrations of metals in aqueous and solid samples.

metals in aqueous solutions. Better detection limits for GFAAS. For example Pb by FAAS ~ 0.19

mg/L Pb by GFAAS ~ 0.012 ng/mL


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Inductively Coupled Plasma (ICP)AtomicInductively Coupled Plasma (ICP)Atomic

Absorption SpectrophotometerAbsorption Spectrophotometer

Inductively Coupled Plasma (ICP) - Plasma

Acoplado por Induccin

Better sensitivity and detection limits than FAAS.

.


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Detection Limits of Various AtomicDetection Limits of Various Atomic

SpectroscopicalSpectroscopical TechniquesTechniques

DetectionDetection LimiLimitmean the lowest concentration that could be detected.

FAASFAAS (Flame Atomic Absorption Spectroscopy), ICPICP--AESAES (Inductively Coupled Plasma

Atomic Emission Spectroscopy), GFAASGFAAS (Graphite Furnace Atomic AbsorptionSpectroscopy, ICPICP--MSMS (Inductively Coupled Plasma Mass Spectrometry)

ICP-MS

0.0001 0.001 0.01 0.1 1.0 10 100 1000

FAAS

ICP-AES

GFAAS

Analyte concentration in g/L (ppb)1g/1L = 1ppt

1mg/L =1ppm1g/L = 1ppb


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Example of Raw Material AnalysisExample of Raw Material Analysis Distinguishing different

polymorphs of lactoseusing Nearinfrared(NIR) spectroscopy

influence flowproperties andmoisture uptake, whichin turn affect blend andcompression behaviour

http://pharmtech.findpharma.com/pharmtech

/Analytical/Ensuring-raw-material-

quality/ArticleStandard/Article/detail/583766


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Example of Raw Material AnalysisExample of Raw Material Analysis NIR spectra of

microcrystallinecellulose of threedifferent particle sizes.

particle size can resultin a poor performanceduring the process,due to difference inparticle in this rawmaterial.


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HPLC (High performance liquid chromatography)HPLC (High performance liquid chromatography)

Is one of the most powerful tools inanalytical chemistry.

It has the ability to separate, identify, andquantitate the compounds that are present inany sample that can be dissolved in a liquid.

Trace concentrations as low asparts pertrillion [ppt] may easily be identified.

HPLC can be, and has been, applied to justabout any sample, such as pharmaceuticals,

food, nutraceuticals, cosmetics,environmental matrices, forensic samples,and industrial chemicals.


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The Basic Liquid ChromatographThe Basic Liquid Chromatograph

The basic liquid chromatograph consists of six

basic units:


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Detectors used in HPLCDetectors used in HPLC UV-vis -10pg

Fluorescence 10fg Refractive Index (RI) 100pg

FTIR 1g

Electrochemical (EC) -100pg

amperometric

NMR novel


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Viable Microorganisms in Raw MaterialsViable Microorganisms in Raw Materials

Mainly aerobes

Microbial limit testing of raw materials-BioburdenBioburden Defined as the quantitative estimation of

the number of viable microorganisms in

material before sterilization. According to standards

Such as USP United StatesPharmacopeia

Example Opportunistic organism such as

Salmonella sp., E. coli, Staphylococcusaureus and Pseudomonas aerginosa


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EndotoxinsEndotoxins Endotoxins are compounds

found in the cell walls of Gram

negative bacteria. These compounds help to form

a semi-permeable membrane

bacteria from threats. Once the bacteria die, the

endotoxins are released, andmany of these toxins cause

health problems in people,animals, and other organisms,hence the toxin in their name.


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EndotoxinsEndotoxins Small, stable, bacterially-

derived hydrophobic

molecules which can easily

contaminate labware and

whose resence can

significantly impact both invitro and in vivo experiments.

Detected by the limulus

amebocyte lysate (LAL) assay

http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mmed&part=A289

(Horseshoe Crab)

Limulus polyphemus


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Water used in the industryWater used in the industry1. Water treatment

systems

2. Storagerequirements

.

4. Different types ofwater used inpharmaceuticals

5. Microbial limits,disinfection


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WaterWater Industry utilizes batch type reactions to

manufacture its products. Cleanliness is an important factor since the

roducts are eventuall consumed b humans.

Water requirements depend on theapplication

Purified water general form

Water for injection (WFI) more stringentrequirements


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Purified Water vs. Water for InjectionPurified Water vs. Water for Injection


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ReferencesReferences Halsey, S. 2009. Ensuring raw material quality.

PharmTech. * From:http://pharmtech.findpharma.com/pharmtech/Analytical/Ensuring-raw-material-quality/ArticleStandard/Article/detail/583766

John, B.A., K.C.A. Jalal, Y.B. Kamaruzzaman and K. Zaleha,

crab blood during bacterial endotoxin invasion. J.Applied Sci., 10: 1930-1936. (en reserva digital)

Riley, B.S. 2004. Rapid microbiology methods in the

pharmaceutical industry. Pharmaceutical Review.* (en

reserva digital)

http://www.fda.gov/

*Artculos asignados para el primer examen parcial.

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