RAW MATERIAL MANAGEMENT

RAW MATERIAL MANAGEMENT

BIOT 4801 Biotecnologa Operacional I UIPR Barranquitas JA Negrn, Ph.D.

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Content
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 in raw material
AAS, ICP IR HPLC Microbiological Endotoxins detection

Water
Purified water Water for injection

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Quality
Quality Assurance (QA)
It is the sum total of the organized arrangements with the objective of ensuring that products will be of the quality required for their intended use.
QA

Good Manufacturing Practices (GMP)

Is that part of Quality Assurance aimed at ensuring that products are consistently manufactured to a quality appropriate to their intended use.

GMP

QC

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 after ascertaining its quality.

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Quality Control
A process employed to ensure a certain level of quality in a product or service.
Analysis of raw materials Analysis in process Analysis finished formulation

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Application 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 Industry

Biological or chemical substances used to manufacture the product
Chemical reagents
Organic, inorganic

Cell culture nutrients Serum components Detergents Anti foam agents Enzymes Cleaning agents Growth factors Chromatographic media Other

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Management of Materials
According to the U.S. Federal Drug Administration FDA, there should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

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Department of Health and Human Services U.S. Food and Drug Administration
http://www.fda.gov/

Responsibility of FDA

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Guidance for Industry Q7A Good Manufacturing Practice (GMP) Guidance for Active Pharmaceutical Ingredients (APIs)
Operations of receipt of materials materials, production, production packaging, packagin repackaging, labeling, repackaging labeling relabeling, relabeling quality control, control release, releas storage and distribution of APIs and the related controls.

Guidance regarding GMP for the manufacturing APIs

http://www.fda.gov/ICECI/ComplianceManuals/Com pliancePolicyGuidanceManual/ucm200364.htm#P20 8_6121

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Raw Material Sampling and Dispensing

Sampling
Sampling needs to be done in accordance with approved written procedures, such as SOPs (standard operating procedure) in order to avoid and/or detect contamination. Most of the samples need to be tested and analyzed for microbial content against the specified limits. So, one has to ensure that during sampling environmental microbes do not contaminate the samples drawn.

Dispensing
Accuracy of weighing is very critical, as any of the weighing errors will affect the composition of final product.

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Verification of Raw Materials

Incoming raw material should not be used until it has been inspected and verified as conforming to the specified requirements. This verification should be in accordance with the requirements of the quality plan or other documented procedures. 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 Incoming Production 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 are exempted from analysis if manufacturer's certificate of analysis is obtained.

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What may be required in a Certification of Analysis?

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Name and Address of Certifying Body Title of Document Description of Material Reference Material Code and Batch Number Description of Certified Reference Material (CRM) Intended Use Instructions for the CRM's Correct Use Hazardous Situation Level of Homogeneity Certified Values and their Uncertainties Traceability Values Obtained by Individual Laboratories or Methods Uncertified Values Date of Certification Period of Validity Further Information Names and Signatures of Certifying Officers

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Example of a Certificate of Analysis

http://www.elannutrition.com/

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Raw Material Analysis

Atomic Absorption Spectroscopy (AAS) Infrared Spectroscopy (IR) HPLC Gravimetric analysis Microbiological tests Endotoxins analysis (LAL)

Portable Raman Spectrophotometer 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, Class 1 elemental impurities As, Cd Pb and Hg 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 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 Absorption 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, which absorb light at characteristic wavelengths.

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Graphite Furnace Atomic Absorption Spectrometry (GFAAS)

It requires a graphite 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 for measuring concentrations of metals in aqueous and solid samples. GFAA has been used primarily for analysis of low concentrations of 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

Electrothermal atomisation

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Inductively Coupled Plasma (ICP)Atomic Absorption Spectrophotometer

Inductively Coupled Plasma (ICP) - Plasma Acoplado por Induccin Better sensitivity and detection limits than FAAS. Various elements can be analyzed simultaneously.

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Detection Limits of Various Atomic Spectroscopical Techniques

Detection Limitmean the lowest concentration that could be detected.
FAAS (Flame Atomic Absorption Spectroscopy), ICP ICP-AES (Inductively Coupled Plasma Atomic Emission Spectroscopy), GFAAS (Graphite Furnace Atomic Absorption Spectroscopy, ICP ICP-MS (Inductively Coupled Plasma Mass Spectrometry)

ICP-MS GFAAS FAAS ICP-AES

0.0001 0.001 0.01 0.1 1.0 10 100 1000

1g/1L = 1ppt 1mg/L =1ppm 1g/L = 1ppb

Analyte concentration in g/L (ppb)

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Example of Raw Material Analysis

Distinguishing different polymorphs of lactose using Nearinfrared (NIR) spectroscopy Polymorphism will influence flow properties and moisture uptake, which in turn affect blend and compression behaviour

http://pharmtech.findpharma.com/pharmtech /Analytical/Ensuring-raw-materialquality/ArticleStandard/Article/detail/583766

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Example of Raw Material Analysis

NIR spectra of microcrystalline cellulose of three different particle sizes. A combination of particle size can result in a poor performance during the process, due to difference in particle in this raw material.

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HPLC (High performance liquid chromatography)

Is one of the most powerful tools in analytical chemistry. It has the ability to separate, identify, and quantitate the compounds that are present in any sample that can be dissolved in a liquid. Trace concentrations as low as parts per trillion [ppt] may easily be identified. HPLC can be, and has been, applied to just about any sample, such as pharmaceuticals, food, nutraceuticals, cosmetics, environmental matrices, forensic samples, and industrial chemicals.

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The Basic Liquid Chromatograph

The basic liquid chromatograph consists of six basic units:

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Detectors used in HPLC

UV-vis -10pg Fluorescence 10fg Refractive Index (RI) 100pg Mass spectrometry (MS) 100pg 1ng FTIR 1g Electrochemical (EC) -100pg
amperometric

NMR novel

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Viable Microorganisms in Raw Materials

Mainly aerobes Microbial limit testing of raw materialsBioburden
Defined as the quantitative estimation of the number of viable microorganisms in or on a medical product, device or raw material before sterilization.

According to standards
Such as USP United States Pharmacopeia

Example
Opportunistic organism such as Salmonella sp., E. coli, Staphylococcus aureus and Pseudomonas aerginosa

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Endotoxins
Endotoxins are compounds found in the cell walls of Gram negative bacteria. These compounds help to form a semi-permeable membrane which is designed to protect bacteria from threats. Once the bacteria die, the endotoxins are released, and many of these toxins cause health problems in people, animals, and other organisms, hence the toxin in their name.

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Endotoxins
Small, stable, bacteriallyderived hydrophobic molecules which can easily contaminate labware and whose presence can significantly impact both in vitro 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

Limulus polyphemus (Horseshoe Crab)

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Water used in the industry

1. Water treatment systems 2. Storage requirements 3. Sampling and testing 4. Different types of water used in pharmaceuticals 5. Microbial limits, disinfection

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Water
Industry utilizes batch type reactions to manufacture its products. Cleanliness is an important factor since the products are eventually consumed by humans. Water requirements depend on the application
Purified water general form Water for injection (WFI) more stringent requirements

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Purified Water vs. Water for Injection

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References
Halsey, S. 2009. Ensuring raw material quality. PharmTech. * From:
http://pharmtech.findpharma.com/pharmtech/Analytical/Ensuring-rawmaterial-quality/ArticleStandard/Article/detail/583766

John, B.A., K.C.A. Jalal, Y.B. Kamaruzzaman and K. Zaleha, 2010. Mechanism in the clot formation of horseshoe 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.