Raw Material Validation

Advanced Pharmaceutical Technology

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Course No: Pharm 5103
Course title: Advanced Pharmaceutical Technology







Submitted To

Submitted By:
Group 2
ID: MS 191131, MS
191132, MS 191133, MS
191134, MS 191135
Pharmacy Discipline,
Khulna University,
Khulna.
Date of Submission: 20
th
October, 2019.

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INDEX

SL
No.
Contents Page
No.
01. Definition of Pharmaceutical Validation
 FDA definition
03
02. Why validation is required 03-04
03. Types of p[harmaceutical validation
 Pre-validation qualification phase of pharmaceutical
validation
 Process validation phase of pharmaceutical validation
 Validation maintenance phase of pharmaceutical validation
04-05
04. Steps of raw material validation 06-13
05. Parameters that are checked
 Physical and chemical raw material analysis
 Chromatography
 Assays
 Impurities
 Microbiological analysis
08-09
06. Importance of validation 13-14
07. Validation protocol 15
08. Pharmaceutical validation report 15-16
09. Reference 17

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Pharmaceutical Validation
The development of a drug product is a lengthy process involving drug discovery, laboratory
testing, animal studies, clinical trials and regulatory registration. To further enhance the
effectiveness and safety of the drug product after approval, many regulatory agencies such as the
United States Food and Drug Administration (FDA) also require that the drug product be tested
for its identity, strength, quality, purity and stability before it can be released for use. For this
reason, pharmaceutical validation and process controls are important in spite of the problems that
may be encountered.[1] Process controls include raw materials inspection, in-process controls
and targets for final product. Even after the manufacturing process is validated, current good
manufacturing practice also requires that a well-written procedure for process controls is
established to monitor its performance.[2]
Validation is an integral part of quality assurance; it involves the systematic study of systems,
facilities and processes aimed at determining whether they perform their intended functions
adequately and consistently as specified. A validated process is one which has been
demonstrated to provide a high degree of assurance that uniform batches will be produced that
meet the required specifications and has therefore been formally approved.
FDA definition of Validation
“Validation is a process of demonstrating, through documented evidence, that a process,
procedure, method, piece of equipment, or facility will consistently produce a product or result
that meets predetermined specifications and quality attributes.”
Why validation is required
Validation in itself does not improve processes but confirms that the processes have been
properly developed and are under control. Adequate validation is beneficial to the manufacturer
in many ways: [3]
• It deepens the understanding of processes; decreases the risk of preventing problems and thus
assures the smooth running of the process.
• It decreases the risk of defect costs.
• It decreases the risk of regulatory noncompliance.

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• A fully validated process may require less in-process controls and end product testing.
Validation should thus be considered in the following situations:
• Totally new process;
• New equipment;
• Process and equipment which have been altered to suit changing priorities; and
• Process where the end-product test is poor and an unreliable indicator of product quality.

Types of pharmaceutical validation

Pharmaceutical validation can be divided into three main phases:
1. Pre-validation qualification
2. Process validation
3. Validation maintenance

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Pre-validation qualification phase of pharmaceutical validation
The pre-validation phase occurs during research and development. This is the planning phase
where all potential parts of the manufacturing process must be considered. This includes pilot
studies, small-batches, and scale-up studies. During this time, attention must be paid to the
details of the process including the establishment of material handling protocols, storage
procedures for raw ingredients and finished product, equipment verification and installation, and
packaging and distribution of final product. Investing time and energy into this initial planning
phase can pay off later in the manufacturing process.

Process validation phase of pharmaceutical validation
Process validation is done throughout the manufacturing process. The ultimate goal is to ensure
that all products are up to code. This ensures a high quality consistent product and decreases the
chance of mistakes or recalls. The main idea is to only allow trained personnel to manufacture
product by following standard operating procedures (SOPs). All materials are handled as
similarly as possible from the transportation and storage phase to the manufacturing phase, all
the way through to the packaging and distribution.

Validation maintenance phase of pharmaceutical validation
The maintenance phase of pharmaceutical validation occurs when the manufacturing process has
been up and running smoothly and consistently for some time. The current SOPs are producing
consistent product and there are no known problems with the process, but it is not time to just
relax and let things ride. In this final phase it is important to regularly review SOPs and
document any changes to the process. There are audits to be done and audit reports to file.
Regular inspections and process oversight are useful as well as additional refresher training for
employees to ensure that they continue to closely adhere to written protocols.
Any regulatory system involving documentation, inspections, training modules, and protocol
updates seems to be mundane and bothersome after a while, but it is extremely important to
do. Pharmaceutical validation is particularly important because the chemicals used to create
pharmaceutical products are extremely sensitive to environmental conditions. It is tiny details
like storage and packaging that can make all the difference in the safety of the final product for
therapeutic use. [4]

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Raw Material
It is a term used to denote starting materials, reagents and solvents intended for use in the
production of intermediates or active pharmaceutical ingredient(API).
Several steps are required to validate a raw material. They are as follows:
(I) LIST ALL THE RAW MATERIALS NEEDED TO PREPARE A PRODUCT BATCH.
The list should include the materials used in production and testing
 Active ingredients
 Excipients
 Processing aids
 Chemicals
 Official standards
 Laboratory materials

Raw material receiving observation sheet
Sl. No. Name of
material
Brand
Name
Date of
receipt
Name of
supplier
Quality
receipt
Invoice
No. &
date





(II) IDENTIFY AT LEAST TWO SUPPLIERS FOR EACH RAW MATERIAL.
The sources of these materials are to be located. It is always advisable to locate and
validate at least two suppliers.

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EVALUATION FOR SELECTING A SUPPLIER:
(1)Provide the raw material that we need
(2)Must be capable of providing the grade that we want
(3)Providing the quantity that we require
(4)To provide increased quantities quickly (to evaluate the supplier ’s capacity)
(5)Determine whether the supplier is a manufacturer or distributor
(6) Cost of the raw material.
(7) Reputation and reliability of the supplier.
 He must use written standard operating procedures and establish proper raw
material storage conditions and distribution procedures.
 Precautions
 Joint agreements
 Attention
 Investigation
(III) IF A SUPPLIER IS NEW
 It is important to establish a good relationship with a supplier.
 To meet representatives personally.
 Inspect his facility
During the visit, it is also important to observe.
 housekeeping and sanitation practiced
 The use of written procedures and logs
 proper segregation and batch identification
 The use of laboratory notebooks
 The size of the laboratory area and staff
 The use of up to date laboratory instrumentation and production
equipment.

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(IV) OBTAIN SAMPLES AND SUPPLIER’S CERTIFICATES OF ANALYSIS
 To determine the characteristics of the raw material.
 The certificates of analysis and samples the extent of variation from lot to lot
on specific tests.
 It is important to measure this variation between different lots from the same
supplier and then the variation between suppliers.




Fig: COA for Acetaminophen (Paracetamol)

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(V) ESTABLISH SPECIFICATIONS FOR EACH RAW MATERIAL
List of parameters.
•For each parameter listed, an acceptable, measurable range of activity should be
established.
•Compendial raw materials
•And non- compendial raw materials

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(VI) ESTABLISH TEST PROCEDURES.
 A test procedure must be established for each specification.
 For raw materials that are compendial, test procedures are denoted along with
their respective specifications.
 For raw materials that are not listed in official compendia, we embark into
methods development.
 This work calls on compendial methods that exist for similar compounds,
which can be modified. It also calls for methods that are published literature.
 Documentation of so developed test procedures should be paid attention.

(VII) ESTABLISH SAMPLING PROCEDURES.
 Documentation of raw material sampling is developed.
 This procedure includes general requirements that may apply to any raw
material received in the plant, such as
 The number of containers to sample(sample size).
 Method of sampling.
 Individual raw materials may have certain sampling requirements based on
their stability and/or intended use.
 Before these individual sampling procedures are instituted in routine practice,
they should be evaluated as part of process validation.

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Raw material sampling observation sheet
Name of material

Claimed grade (IP/BP/USP)

Import/ Mfg LIC No.

Name & Address of Manufacturer

Name of Packer/ Trader if any

Inner lining of bags

Checked against Specification No

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Observation during sampling:
1. Form :
2. Odour : Sampled by:
3. Spillage if any : Sample handed
4. Colour over to :
5. Foreign matter: Name: Date: Ref. No:

(VIII) ESTABLISH OPTIMUM STORAGE CONDITIONS
 Raw material containers must be handled and stored under prescribed
conditions in order to protect their stability over the stated shelf life.
 The chemistry of each raw material should be reviewed and aspects
concerning hygroscopity, sensitivity to light,sensitivity to high and low
temperature extremes, ability to support microbial growth,reactivity with any
container or closure system, and oxidising capability are checked.
 Once we have established the factors that critically affect a raw material, we
can conduct stability studies that will indicate the optimum storage conditions
and establish a shelf life for the raw material.

(IX) ESTABLISH SHELF LIFE
 Shelf life or expiry dating of a raw material is the time period within which it
must be used.
 Sometimes we assign an expiry date that is shorter than our data indicate, so
that we will always use fresh raw materials.
 The shelf life of a raw material is established by testing over time in the
containers and closures to be used, after storage under the anticipated
optimum conditions, and also under adverse conditions.

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(X) CHALLENGE OF THE RAW MATERIALS.
 The last step required to validate a raw material is the operation in which the
information that has been established concerning the raw material is
challenged, to assure that is scientifically sound and meaningful.[5-7]
Parameters that are checked:
 Physical and chemical raw material analysis
 Boiling point
 Clarity and degree of opalescence of liquids
 Degree of coloration of liquids
 Density of solids
 Elemental analysis (atomic absorption, atomic emission, graphite furnace, hydride system)
 Freezing point
 Identification testing
 Infrared spectrometry
 Limit tests
 Melting point
 Optical rotation
 Osmolality
 pH
 Refractive index
 Titration (amperometric, complexometric and potentiometric)
 UV-VIS spectrometry
 Viscosity (capillary and rotating)
 Water determination (loss on drying and Karl Fisher)
 Chromatography
 Gas chromatography
 High performance liquid chromatography
 Ultra-performance liquid chromatography

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 Assays
 Acid value
 Ester value
 Hydroxyl value
 Iodine value
 Peroxide value
 Saponification value
 Gas chromatography
 High performance liquid chromatography (HPLC)
 Titrations
 Ultra-performance liquid chromatography (ULPA)

 Impurities
 Ethylene oxide and dioxan
 Gas chromatography
 High performance liquid chromatography
 Particulate matter
 Residual solvents
 Ultra-performance liquid chromatography
 Atomic absorption, atomic emission, graphite furnace, hydride system

 Microbiological analysis
 Absence of specific micro-organisms
 Bioburden, TAMC and TYMC
 Endotoxin testing (gel clot method, kinetic turbidimetric method)
 Microbiological assay of antibiotics
 Sterility testing [8]

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Importance of Validation Process
It would not be feasible to use the equipment without knowing whether it will produce the
product we wanted or not.
 The pharmaceutical industry uses expensive materials, sophisticated facilities &
equipment and highly qualified personnel.
 The efficient use of these resources is necessary for the continued success of the
industry. The cost of product failures, rejects, reworks, and recalls, complaints are the
significant parts of the total production cost.
 Detailed study and control of the manufacturing process- validation is necessary if
failure to be reduced and productivity improved.
 The pharmaceutical industries are concerned about validation because of the following
reasons.
 Assurance of quality.
 Cost reduction.
 Government regulation [9, 10]

Validation Protocol [11]
The validation protocol should be numbered, signed and dated, and should contain as a minimum
the following information:






t

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Manufacturing Records









The Validation Report
The validation report [12-14] should contain the approved validation protocol, tabulated or
graphical results, process monitoring (forms) and all analytical results of the validation batches.
The validation report should have a conclusion that explains the manufacturing specialist’s
statement and opinion stability testing on all validation batches must be performed according to
the protocol, according to NDA/ANDA stability plan.

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References

1. Sharp, J., The problems of process validation. Pharm J, 1986. 1: p. 43-5.
2. Chow, S.-C., Pharmaceutical validation and process controls in drug development. Drug
information journal, 1997. 31(4): p. 1195-1201.
3. Jatto, E. and A.O. Okhamafe, An Overview of Pharmaceutical Validation and Process Controls
in Drug Development. Tropical Journal of Pharmaceutical Research, 2002. 1(2): p. 115-122.
4. Martínez, L.M., Pharmaceutical Validation. Thu, Sep 13, 2018.
5. committee, B.a.p.i., Validation in API manufacturing plants.
6. Administration., W.D.u.F.a.D., Guide to Inspections Validation of Processes.
7. Convention, T.U.S.P., Validation of compendia Methods. 1995.
8. Laboratories, S., Raw Material Analysis for APIs and Excipients.
9. Gupta, G., R. Garg, and S. Aggarwal, Guidelines on General Principles of Validation: Solid.
Liquid and Sterile dosage forms, 2008. 6(1).
10. FDA, D.G., Process Validation: General Principles and Practices. 2008, November.
11. Sandhya, C., et al., Process validation: An essential process in pharmaceutical industry.
International Journal of Advances in Scientific Research, 2015. 1(04): p. 179-182.
12. Jena, S., et al., Industrial process validation of solid dosage forms-An overview. Int J Pharm Sci
Rev Res, 2010. 4(2): p. 145-54.
13. Akers, J., Simplifying and improving process validation. PDA Journal of Pharmaceutical Science
and Technology, 1993. 47(6): p. 281-284.
14. Agalloco, J., Validation: an unconventional review and reinvention. PDA journal of
pharmaceutical science and technology, 1995. 49(4): p. 175-179.