PHARMACEUTICAL ANALYSIS II

PCH302 (AY 2021-2022)

Mr. Von Jay Maico Gabucan, RPh

TOPIC 1
INTRODUCTION TO PHARMACEUTICAL ANALYSIS
Quality Control with Emphasis To Instrumentation Methods Of Analysis

PRELIMINARIES QUALITY CONTROL VS QUALITY ASSURANCE

OBJECTIVES
• Acquire a basic understanding of the principles behind QC QA
instrumental methods of analysis Deals with product Deals with process
o E.g. spectrophotometry, chromatography, and Focus on testing; Focus on building in quality;
electrometry etc detecting defects preventing defect
• Apply the principles and techniques on prepared or Results of what we’ve Ensures we’ve done the
commercially procured pharmaceutical products done are what we right thing the right way
• Develop awareness and appreciation of the pharmacists expected
concerning product quality Common corrective Preventive process
• Discuss quality control process & validation procedures process
• Application of stability tests and statistical quality control
and interpret results obtained as acceptable or rejectable FUNCTIONS OF QC
based on criteria set 1. Analysis fx
• Assure acceptability of product
OUTLINE • All materials are w/in specs
• Review the definition of terms in QA/QC
• Demonstrate understanding of the terminologies used in the 2. Monitor fx
pharmaceutical analysis • In process testing
• Appreciate the importance of quality control, statistics and • Deviation reports
sampling plan, materials, and manufacturing, packaging,
• Environmental monitoring
distribution control
3. Record, Review, & Release (3R) fx
PHARMACEUTICAL MANUFACTURING
• BPR (Batch Manufacturing Method), analysis report
REQUIREMENTS
• Must comply with cGMP 4. Audit fx
• Must meet quality standards
• Detect areas where SOPs (Standard Operating
• Must follow FDA regulations Procedures) are not followed

IMPORTANCE OF QC
Ensure: Equipment validation
✓ Consistency ✓ Specificity
✓ Comparability ✓ Detection limit
✓ Accuracy ✓ Quantitation limit
✓ Precision ✓ Linearity
✓ Equipment ✓ Range
✓ Robustness
DIVISIONS OF PHARMACEUTICAL MANUFACTURING TWO TYPES OF ANALYSIS
1. Regulatory division
2. Marketing division QUALITATIVE analysis QUANTITATIVE analysis
3. Human resource division Answers “WHAT? Answers “HOW MUCH?
4. Engineering division Chemical entity identified, Determines the amount of
5. Quality assurance division positive or negative, component
6. Quality control division present or absent

Organizational hierarchy

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SAFETY, EFFICACY, QUALITY WHO Expert Committee on Specifications for

- 3 pillars of drug product Pharmaceutical Preparations
- Safety & efficacy aren’t separated from quality but part of it - History: met from 9-12 Oct 2012
- Had provided considerable support to the WHO
Quality Prequalification of Medicines Programme
- Conforms to standards - Ensured that drug product specifications for drug products
o “making it right the first time” are met to provide unified international standards of quality,
o Totality of features and characteristics of product safety, and efficacy
and services that bears on its ability to satisfy both
implied and stated needs ASEAN STANDARDS for pharmaceuticals
- Conforms to standards like - Association of Southeast Asian Nations
o Laws for legal aspects - Countries: IDN, MYS, PHP, SGP, THA, BRN, VNM, LAO,
o cGMP & PIC/S for process related aspects MMR, KHM
o Pharmacopoeias for product related aspects o Indonesia, Malaysia, Philippines, Singapore,
▪ Contains set standards & specifications Thailand, Brunei, Vietnam, Laos, Cambodia
as basis for accepting or rejecting a - Obj: to develop harmonization schemes of pharmaceutical
product regulations of the ASEAN member countries to complement
and facilitate objectives of AFTA (ASEAN Free Trade Area)
Quality in Pharmaceutical Industries - Develop technical requirements
current Good Manufacturing Practices (cGMP) - Ultimate goal: elimination if technical barriers to trade
- USFDA based, mandatory posed by regulations
- Specific practices that ensure quality of product and assure
- ID, strength, quality and purity of product through proper ASEAN Harmonized Standards for Pharmaceutical
design monitoring process and facilities finally preventing products
instances of contamination, mix ups, failures and errors Prepared documents include:
- Organisation dossier
PIC/S - Variation guideline for pharmaceutical product
- Guideline for the conduct of bioequivalency studies
- European based, orange book = voluntary
- Guideline in stability study of drug product
- Pharmaceutical Inspection Convention
- Guideline on analytical validation, etc.
- Pharmaceutical Inspection Co-operation Scheme
- Adopted to further facilitate the removal of barriers to trade
QUALITY IN REAGENTS
in medicinal product
- Must be pure and must conform to USP/NF
ICH – quality guidelines
Reagent Grades (different grades for different purposes)
- International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Reagent - high quality chemical for laboratory use
Human Use ACS - Meet or exceed purity standards of ACS
(American - acceptable for food, drug, or medicinal
- Consist of quality, safety, efficacy, & multidisciplinary
Chemical use,
guidelines
Society) - purity of ≥ 95%
QUALITY GUIDELINES Guaranteed - For laboratory & analytical chemistry
- Stability studies Reagent - Meets or exceeds ACR requirements
- Defining relevant thresholds for impurities testing (GR)
- More flexible approach to pharmaceutical quality based on Analytical - high purity reagents, best suited for
GMP risk management Reagent analytical applications
(AR) - ideal for providing consistent results
QUALITY GUIDELINES CONSIST OF Purified - Good quality (meets no official standard)
1A – 1F Stability Grade / - Limited to Inorganic chemicals
2 Analytical method validation Practical - For education only
3A – 3D Impurities Grade
4A – 4B Pharmacopoeia Laboratory - Solvents for general laboratory appltns
5A – 5E Quality of biotech products Grade - Impurity level unknown
6A – 6B (6) Specifications USP grade - Meets USP requirements, purity of ≥ 95%
7 GMP NF grade ­ Meets NF requirements
8 Pharmaceutical devt Technical ­ general use (commercial & industrial)
9 QRM (quality risk management) grade ­ Lowest and cheapest grade
10 PQS (pharmaceutical quality system) ­ Purity around 85-90%
11 Devt & manufacture of drug subs Primary ­ reagent for which we can dispense an
12 Lifecycle management Standard accurately known amount of analyte

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PHARMACOPOEIAS
­ Contains drug monographs with set specifications for
identity, strength, quality, purity, packaging, and labelling for
substances and dosage forms
­ Contains standards for medicines, dosage forms, drug
substances, excipients, and other therapeutics

DIFFERENT PHARMACOPOEIAS
1) United States Pharmacopoeia – drug monographs
2) National Formulary – excipients
3) British Pharmacopoeia
4) European Pharmacopoeia
5) Japan Pharmacopoeia

USP/NF
­ Revised annually since 2002
­ 2 supplements in a year
­ Founded in 1820

General chapters:
<1000 general notice, monographs
1000-1999 informational purposes only
≥2000 dietary ingredients / supplements

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MATERIAL, MANUFACTURING, PACKAGING,

DISTRIBUTION, STATISTICAL CONTROL
FISHBONE DIAGRAMS

Information Inside A Receiving Tally Report

✓ Date received ✓ Sampled and inspected by
✓ Supplier ✓ Analytical report #
✓ Quantity ✓ Conclusion of report
✓ Unit ✓ Reason
✓ Description ✓ Tested by:
✓ Container ✓ Disposition
✓ Received by ✓ Signatories

Material Control Types

­ Stock control
­ Scheduling of requirements
­ Purchasing
­ Receiving and inspecting
BASIC GMP PROCESS ­ Storing and issuing
1) Material Control Material control also includes inventory
2) Manufacturing Control
3) Packaging Control Techniques in Inventory Control
4) Distribution Control a) ABC – Always Better Control
­ emphasizes % value of consumption
MATERIAL CONTROL ­ Advantages: Strict control is exercised
Basic GMP Process ­ Investment in inventory is reduced
GOALS IN MATERIAL HANDLING ­ Storage cost reduced
­ Increase accuracy and reduce errors ­ Management time saved
­ Utilize your space better
Control mechanism of ABC
­ Adapt your operation for future growth - thinking in decades Item A B C
­ Reduce operational costs Safety No, very
­ Reduce injuries and operate safer Low High
stock low
­ Get your operation running fast Expediting,
Follow up Max Periodic
exceptionally
MATERIAL CONTROL Value
­ Definition: systematic control over the purchasing, storing, Rigorous Moderate Minimum
analysis
and using of material to minimize possible cost Handled Senior Middle level Fully
­ Utilizes RTR – receiving tally report by officials managers delegated

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b) JIT – Just In Time Stickers

­ purchase only when in demand Red rejected
Green approved
Advantages: Yellow quarantine
­ Investment in inventory is reduced
­ Carrying cost is reduced PRINTED AND PACKAGING MATERIALS
­ reduction in number of possible suppliers to deal with Minimum criteria for printed materials
is reduced ✓ Text ✓ Cleanliness
­ Minimum possible wastage ✓ Color ✓ Shape
✓ Size ✓ Adequate Paste
c) PIS – Perpetual Inventory System ✓ Thickness ✓
­ System of records
­ physical movement of stocks & their current balance CONTAINERS
Physical inspection
✓ Shape ✓ Color
✓ Volume ✓ Light Transmission
✓ Leak ✓ Height

Physico-chemical tests
✓ ID
✓ thermal analysis
✓ moisture

CLOSURES
­ Must be studied for the overall stability program
­ Must not react chemically or physically with the product
­ Must not absorb materials from formulation or leach its
d) VED – Vital, Essential, Desirable ingredients
o Ex. BHT (butylated hydroxytoluene) in plastics
­ depending on criticality for production
­ Control of spare parts
Torque
absence even for a short time will stop ­ a measure of circular force used to tighten
Vital the cap, unit of force is inch pound
production for quite some time
(2)
ie. disintegrant ­ TORQUE TESTER – to check the
Absence cannot be tolerated even for a few tightness
Essential
hrs, production will not continue w/out them ­ Control of cap tightness (avoid evaporation
(1)
Ie. vit C (API) or leakage of product)
needed items but absence even for a week ­ Excessive TORQUE may break the closure
Desirable
will not stop production
(3)
ie. Yellow colorant
MANUFACTURING CONTROL
e) FSDN – Fast, Normal, Slow, Dead moving
­ frequency of use Basic GMP Process
­ Manufacturing process controls include all systems and
Fast consumed in a short amount of time software that exert control over production processes
Slow expected to be exhausted over a period
Dead consumption is almost nil DOCUMENTS IN MANUFACTURING CONTROL
Normal normal moving 1. Manufacturing monograph – where master formula and
batch production records are based
2. QC monographs – quality of each component
f) HML – High, Medium, Low value 3. Batch records
­ unit value of stock (unit will be determined by you) 4. SOP (Standard Operating Procedures)
o ie. Percent purity
­ Same as ABC MANUFACTURING CONTROL PROCESS
1. Raw Materials QC
2. Production (includes in process QC)
3. End Product QC

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RMQC BATCH VS LOT

Identification ✓ Chemical test BATCH Specific amount produced in a unit time or
test ✓ Physical test according to a single manufacturing order
✓ Instrumental methods LOT a portion of a batch
Purity test ✓ Assays
Limit test ✓ Gross impurities PACKAGING CONTROL
✓ Biological impurities Basic GMP Process
Physical test ✓ Specific gravity (spgr)
REASONS:
✓ Solubility
✓ Refractive index 1. To assure that products have met the standards and specs
✓ Optica activity shall be distributed to the market
✓ MP/BP 2. To prevent mix-ups and errors
Special test APAP (N-acetyl-para-aminophenol) 3. Correct labels are employed
4. Finished product is identified with a control code
­ Test for:
o p-chloroacetanilide
o p-aminophenol DISTRIBUTION CONTROL
Basic GMP Process
Quinine Sulfate ­ Stock card – indicates beginning and an ending inventory
­ dihydroquinone sulfate within a certain period
­ CERTIFICATE ANTIBIOTICS AND INSULIN – w/held from
IPQC distribution until BATCH CERTIFICATE from FDA is
Primary Moisture received
Adequacy of Wetness
Shape STATISTICAL QC
Final Moisture → 0.5% to 1% ­ Sampling plan: military std or square root formula
Primary Moisture ­ Control chart:
Adequacy of Wetness UCL = X + 3SD
Shape LCL = X - 3S
Final Moisture
Angle of Repose Static AoR SAMPLING PLANS
Kinetic AoR Military Standard
Porosity
a. MIL-STD-105D
Bulk & Tapped Density
b. ABC-STD-105D
Carr’s Index
Hausner’s Ration
Particle Size Distribution

IN-PROCESS QUALITY CONTROL (IPQC)

­ performed to determine if the product meets specifications
throughout processing period
­ any out of range can be corrected before further processing

BATCH REPRODUCTION RECORD

­ Accurate reproduction of master formula

N plan
n = N + 1

p plan
p = (N)(0.4)

r plan
r = (N)(1.5)

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Material Supplier Identification FORMULA SHEET

uniformity credibility test STATISTICAL QC
N ✓ ✓ UCL = X + 3SD
p ✓ ✓ LCL = X - 3S
r X X
SAMPLING PLANS
DOUBLE SAMPLING n plan = N + 1
DEFINITION p plan = (N)(0.4)
­ Double sampling is taking a second set of samples in a one- r plan = (N)(1.5)
stage survey because the retrospective power of the test
did not meet design objectives (ie first criteria). DOUBLE SAMPLING
o so, the sampling will be repeated and the criteria Range = API ± (API)(%)
is doubled
­ At the same time, double sampling causes the Type I error
rate to exceed the rate specified for the one-stage survey.

SAMPLE SITUATION
1. Do a tablet variation test

2. Take 20 tablets & individually weigh them

a. Standard: 550 mg API
b. Allowable deviation: 10%

3. Get the range using the allowable deviation

Range = API ± (API)(%)
a. LCL = 550 – (550)(0.1) = 495
b. UCL = 550 + (550)(0.1) = 605
c. Range = 495 mg to 605 mg

4. One tablet weighs 609 mg, which is beyond the range

a. Failed the first criteria
b. Second criteria = 2 x (10%) = 20%

5. After doubling the criteria, take ANOTHER 20 TABLETS

6. Test the tablets using the second criteria = 20%, a tablet

weighed 610 mg
a. Range = 440 mg to 660 mg
b. 610 mg is w/in the range
c. Accept the 40 tablets

7. When any tablet exceeded the second criteria range, reject

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