QUALITY MANAGEMENT IN THE DRUG INDUSTRY

● Pharmaceutical and cosmetic manufacturing is recognized as a major industry which requires a clearly defined
organization. Each segment of this organization is expected to fine-­‐tune its functions and responsibilities.
● An effective coordination is called for among its personnel, equipment, building and inventory of materials.
● All these activities are performed towards the production of a drug or cosmetic of the highest standard and at the
lowest cost.

● All products are required to have quality.

● May have a different basis of “quality”
○ Eg. shampoo has different characteristics than lotion
○ For every product, there has to be quality parameters or attributes.

● Total quality management: like an “umbrella”

● Quality initiative requires investment and is sometimes perceived as “extra work”
○ If no quality investment = failure cost (wherein you still pay more because of rejects, bad company image, etc)
○ Appraisal cost → what we usually encounter; “quality testing” that ensures the quality of the product
○ Prevention cost → highest form; you’re not just using the money to test or compensate for the quality but you
are using your resources to prevent low-quality products

● In the drug industry at large, quality management is usually defined as the aspect of management function that
determines and implements the “quality policy”, i.e. the overall intention and direction of an organization regarding
quality, as formally expressed and authorized by top management.
○ Quality policy → statement of an organization's commitment to quality.
■ It is common to see a copy of the quality policy posted in conspicuous places in a company.
○ As part of QMS, several organizations have implemented quality systems, eg. ISO
■ ISO → example of a quality system that is an infrastructure that covers the organizational structure for
quality management, sets up procedures and processes, and ensures the availability of resources.
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● Quality system: ISO
○ Certifies the system and not the product (even with ISO, it does not mean that the system is perfect)
○ Not industry specific
○ ISO certified → good process more or less
○ Three minimum requirements:
■ 1. documented quality system (written tasks, responsibilities, documents, records, feedbacks, etc)
■ 2. IQA (within the organization, spot-checking)
● We also have external auditors (other institutions)
■ 3. CAPA (a mechanism to prevent errors to happen again)

● The basic elements of quality management are:

○ an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures,
processes and resources;
○ systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given
requirements for quality. The totality of these actions is termed “quality assurance”.

● Within an organization, quality assurance serves as a management tool.

● In contractual situations, quality assurance also serves to generate confidence in the supplier.
● The concepts of quality assurance, GMP and quality control are interrelated aspects of quality management.

● Quality assurance (QA), although commonly identified as simply documentation, is the overall organizational body
designed to assure product quality.
○ It is a wide-‐ranging concept covering all matters that individually or collectively influence the quality of a
product.
○ It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the
quality required for their intended use.
○ Quality assurance therefore incorporates GMP and other factors, including product design and development.
■ QA as GMP → ensures that products are consistently produced and controlled to the quality
appropriate for the intended use and satisfies marketing authorization for product registration
requirements.
○ In a distribution company, QA is represented as Good Distribution Practices (GDP).
○ In a laboratory, QA is represented as Good Laboratory Practices (GLP).

● The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are
fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at
risk due to inadequate safety, quality or efficacy.
● The attainment of this quality objective is the responsibility of senior management and requires the participation and
commitment of staff in many different departments and at all levels within the company, the company’s suppliers,
and the distributors.
● To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system
of quality assurance incorporating GMP and quality control.
● It should be fully documented and its effectiveness monitored.
● All parts of the quality assurance system should be adequately staffed with competent personnel, and should have
suitable and sufficient premises, equipment, and facilities.

● Good manufacturing practice (GMP) is that part of quality assurance which ensures that products are consistently
produced and controlled to the quality standards appropriate to their intended use and as required by the marketing
authorization.
○ GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical production.
■ Such risks are essentially of two types:
● cross­‐contamination (in particular of unexpected contaminants)
● mix-­‐ups (confusion) caused by, for example, false labels being put on containers.

● Quality control (QC) refers to the sum of all procedures undertaken to ensure the identity and purity of a particular
pharmaceutical.
○ It is a tool which gives the assurance that a product conforms to standards and specifications through a
system of inspection, analysis, and action.
○ Such procedures may range from the performance of simple chemical experiments which determine the
identity and screening for the presence of particular pharmaceutical substance (thin layer chromatography,
infrared spectroscopy, etc.), to more complicated requirements of pharmacopoeial monographs.
○ Activities extend to the area of quality control laboratories (good laboratory management practices, models,
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 e.g. for certificate of analysis and lists of laboratory equipment, and an external assessment scheme (WHO
website)
○ QC is a section covered under GMP.

● Quality control is defined in the European Union guidelines as that part of GMP that is concerned with sampling,
specifications, testing and with the organization, documentation and release procedures which ensure that the
necessary and relevant tests are actually carried out and that materials are not released for use, nor products released
for sale or supply, until their quality has been judged to be satisfactory.
● Quality control can have no effect on the quality of the product. It is merely a measuring process.

The relationship between quality management, QA, GMP and QC can be viewed as a type of cascade arrangement as shown in
Figure 1.

● Quality management, with the overall policy of the organization towards quality, comes above everything else. Next
comes quality assurance, which is the unit that ensures the policy is achieved.
● GMP is a part of quality assurance; it deals with risks that cannot be tested and builds quality into the product.
● Quality control is a part of GMP: the part that is focused on testing of the environment and facilities, as well as testing
of the materials, components and product in accordance with the standard.

● Quality is the suitability of either a drug substance or drug product for its intended use.
○ This is the combination of attributes or characteristics (i.e., identity, strength, and purity) of a product which,
when compared to a standard, serves as a basis for measuring the uniformity of the product and determines
its degree of acceptability.
○ The quality of drug substances and drug products is determined by their design, development,
in-­‐process controls, GMP controls, and process validation, and by specifications applied to them throughout
development and manufacture.
○ Desirable product characteristics are product specific.
■ Eg. Shampoo vs Lotion → it is desirable for a shampoo to be foamy but if the same property is applied
to lotion, it would be considered unacceptable.
○ It has several measurable criteria:
■ 1. Conformance → product within prescribed limits for the product parameters
■ 2. Fitness for use → ability of the product to function as intended
■ 3. Reliability → a related criterion that refers to functionality in a specified environment for a definite
length of time
■ 4. Yield → having a high degree of acceptable units produced
■ 5. Customer satisfaction → ensures product’s safety, purity, and efficacy

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● In enforcing current GMP to achieve the desired goal of delivering a safe, pure and effective product at the lowest cost
to the consumer, a specific group must be organized to be the core of the company’s quality audit program.
● Thus, the quality control department is organized to maintain the quality of products to a prescribed level.
● The most effective organization establishes direct reporting from quality control department to top management.
● The structure in Figure 2 is recommended to avoid conflict of interest in a manufacturing firm.

● The overarching philosophy articulated in both the current GMP regulations and in robust modern quality systems is:
Quality should be built into the product, and testing alone cannot be relied on to ensure product quality.

● With this responsibility, a quality control system is established at the conception of a new product, during production
of the batch, and during distribution of the commercial package.
● This system is a combination of those administrative and technical procedures which must be used to produce and
deliver a safe, pure, and effective product to the end user.

● The potential benefits derived from a quality control system are as follows.
1. The system minimizes or eliminates the risk of marketing unsafe products.
2. It guarantees conformance to regulatory requirements.
3. It guarantees product efficacy.
4. It reduces operating cost.
5. It reduces operating losses.
6. It produces higher employee morale.
7. It motivates the pharmaceutical/medical professions to sell or prescribe the product.

Figure 2. Reporting responsibilities in a manufacturing firm.

● In a manufacturing environment, variety of people will have apparently different goals – from increasing pressures on
costs, to increasing technical and validation requirements, and finally to quickly release the products to the
marketplace.
● In this position, the pharmaceutical manufacturing personnel are faced with an apparently irreconcilable set of
objectives to achieve. The cost of quality will help to achieve all the objectives in one go.

● Cost of quality is a tool that has been used in many industries, usually within a total quality management or
performance improvement programme. There are three main types of quality costs:
■ Although the implementation of the QMS comes with great benefits, it admittedly comes with a cost.
However, the absence of a mechanism to ensure quality in an organization can be equally or more
often more costly.
■ Three types of quality cost: the first is associated with lack of quality and the other two includes cost
invested to ensure quality.
○ 1. Failure costs (costs of non–quality) are those associated with getting things wrong. They can be tangible
costs, such as the cost of rejects or “reworks”, or they can be intangible costs, such as lost sales, damage to
image or problems with the regulatory authorities.
■ Commonly, start-up companies may have more failure costs.
○ 2. Appraisal costs are those associated with checking that things were done correctly. It should be emphasized
that this is not value-­‐adding activity of itself; it is merely an historical measurement of what has
already happened.
■ Eg. QC test conducted before, during, and after production
■ Over time, good organizational management should result in a shift to higher appraisal and prevention
costs.
○ 3. Prevention costs are the costs associated with making sure that things will be done right. This is the one
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 activity of the three that can be considered to be value adding.
■ Eg. Company investment for employee training and audits

● All the activities related to quality are measured and categorized as failure, appraisal or prevention costs.
● By highlighting the various costs in this way, it makes it easy to decide where to focus efforts in order to improve
performance and also reduce costs.

STANDARDS AND SPECIFICATIONS

● A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria,
which are numerical limits, ranges, or other criteria for the tests described.
○ It establishes the set of criteria to which a drug substance or drug product should conform to be considered
acceptable for its intended use.
○ "Conformance to specifications" means that the drug substance and/or drug product, when tested according
to the listed analytical procedures, will meet the listed acceptance criteria.
○ Specifications are critical quality standards that are proposed and justified by the manufacturer and approved
by regulatory authorities as conditions of approval.

● Specifications are one part of a total control strategy for the drug substance and drug product designed to ensure
product quality and consistency.
○ Other parts of this strategy include thorough product characterization during development, upon which
specifications are based, and adherence to Good Manufacturing Practices; e.g., suitable facilities, a validated
manufacturing process, validated test procedure, raw material testing, in-­‐process testing, stability
testing, etc.
● Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full
characterization, and should focus on those characteristics found to be useful in ensuring the safety and efficacy of
the drug substance and drug product.
● In a product, specifications must cover the following points:
1. Formula: This is concise and precise statement of the ingredients that comprise the product, together with the
percentage and/or weight of each.
2. Raw material specification: This should enumerate the characteristics of all materials that go into the product
and the permissible range of purity of each ingredient. Deviation beyond this range may be expected to cause
failure of the product to function as planned, or, at least, result in an undesirable lack of uniformity. Standard
compendia like the USP, NF, BP, Merck Index, etc., provide this valuable information.
3. Standard operating procedure: This is a step by step method on how to go about a job. It must spell out all
information and instructions that assure that variations in production from day to day and week to week will be
held to within acceptable established ranges.
4. Finished product specification: This should cover all characteristics that affect the proper performance, purity,
safety, and stability of the product. Tolerances may be minimum, maximum, or both, depending on the nature of
the situation.
5. Packaging material standard: This should be set for everything that goes around the product, i.e., bottles, cans,
aluminum foil, cellophane, jars, caps, cap liners, labels, printed inserts, cartons, wrapping papers, and shipping
cases. Packaging must be considered with the following points in mind:
a. The units may have to run on a high-­‐speed line.
b. They may involve a complicated assembly.
c. The package may be functional.
d. The package must be completely compatible with the product.
e. The package must protect the product and assure its stability,
f. The package must ship well.
6. Testing methods: These are indispensible in assuring conformity to standards. Since they play such a vital role,
testing procedures must be standardized so that they yield results of comparable precision and accuracy in
the hands of different operators and laboratories. The tests must be validated to ensure precision and
accuracy on application.

● A standard is a document that provides requirements, specifications, guidelines or characteristics that can be used
consistently to ensure that materials, products, processes and services are fit for their purpose (ISO).
○ ISO International Standards ensure that products and services are safe, reliable and of good quality.
○ The ISO 9000 family addresses various aspects of quality management and contains some of ISO’s best
known standards.
○ The standards provide guidance and tools for companies and organizations who want to ensure that their
products and services consistently meet customer’s requirements, that quality is consistently improved and
that the system is being operated effectively.

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 ○ Standards in the ISO 9000 family include:
■ ISO 9001:2008 -­‐ sets out the requirements of a quality management
system (QMS) ISO 9000:2005 -­‐ covers the basic concepts and language
■ ISO 9004:2009 -­‐ focuses on how to make a quality management system
more efficient and effective ISO 9011:2011 -­‐ sets out guidance on internal
and external audits of quality management systems.

● To establish material or product conformance, we commonly compare product

characteristics to standards.
● Pharmacopeial standards
○ Found in published monographs
○ USP/NF, BP, EP, PP
■ At the moment, we only have the first edition of PP which provides
standards for crude drugs found locally.
■ Sometimes, FDA or other regulatory agencies may impose some standards
which are not covered in the pharmacopeia.
○ Identity, physical tests, purity tests, alcohol content, assay
○ USP: every year revision; electronic copies are more favored
○ USP: actives are listed, NF: excipients are listed
● Regulatory standards
○ Mandated by the regulatory agencies
○ Priority: safety and efficacy
■ Sometimes, regulatory agencies may request for limit tests (for toxic APIs,
etc)
○ Phil. FDA, WHO, US FDA
○ For registration purposes
■ Compliance with regulatory standards is important for product registration
processes.
● In-house standards
○ Unofficial
■ Not found in the compendium but are similarly required to ascertain
product quality that complies with GMP.
○ Generated by the manufacturer
○ Allow flexibility
○ Mandatory in compliance to GMP
○ Examples: color or size → although these parameters are not included in the
official monograph and the FDA will not dictate the specific color or the size you
manufacture, it does not mean that the company does not need standards for
them.
■ When you fail to ensure consistency of color or size with every batch of
production, you create an impression of a lack of quality.

ISO 9001
● Standards for worldwide trading
○ An ISO 9000 certification in the Philipines means exactly the same as the ISO 9000
certification in other parts of the world, meaning they passed the same standard.
● Certify a management system and not the quality of goods produced
○ If the quality system is being effectively implemented, then we can expect quality
products from the company.
● Certification achieved through a third-party assessment
● ISO 9000 quality system may be applied to different industries: hospitals, schools,
manufacturing companies, etc.
● The three essential elements of ISO 9000 are:
○ 1. Documented quality system → quality manuals covering documented procedures
and read-in instructions standard forms among others
○ 2. Internal quality audit system → personnel within the company checks for the
compliance of documented procedures.
■ Usually what happens is that one department checks the compliance of
another department.
■ IQA may be outsourced by the company; you can hire external auditors to
do the quality audits.
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 ○ 3. Corrective and preventive action system (CAPA) → this shows that the company
is serious about continuous improvement.
■ Having a quality system in place does not mean that there is a perfect
system; but the system should have a mechanism for implementing
corrective and preventive system.

● In recent years, the ICH introduced the concept of pharmaceutical quality system (PQS).
● The idea of ICH Q10 is the integration of GMP and quality systems.
○ GMP supplied from the technology transfer group product discontinuation.
○ PQS elements are intended to complement GMP standards toward ensuring the consistent manufacturer
products that needs specifications.

● The organization shall establish, document, implement and maintain a quality management system and continually
improve its effectiveness in accordance with the requirements of this International Standard.
1. The quality management system documentation shall include:
a. Documented statements of a quality policy and quality objectives,
b. A quality manual,
c. Documented procedures required by this International Standard,
d. Documents needed by the organization to ensure the effective planning, operation and control of its
processes, and
e. Records required by this International Standard

2. The organization shall conduct internal audits at planned intervals whether the quality management system
f. Conforms to the planned arrangements to the requirements of this International Standard and to the quality
management system requirements established by the organization, and
g. Is effectively implemented and maintained.

3. The organization shall continually improve the effectiveness of the QMS through the use of the quality policy, quality
objectives, audit results, analysis of data, corrective and preventive actions and management review.
h. The organization shall take action to eliminate the cause of nonconformities in order to prevent recurrence.
Corrective actions shall be appropriate to the effects of the nonconformities encountered.
i. The organization shall determine action to eliminate the causes of potential nonconformities in order to
prevent their occurrence. Preventive actions shall be appropriate to the effects of the potential problems.

QUALITY VARIATION
● Quality variations or non-conformities are controlled by standards and specifications.
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● Quality variations may be random or due to chance or brought about by assignable causes.
○ Assignable causes: materials, methods, man, and machine
● When left uncontrolled, errors may proliferate leading to defective products.

● Quality characteristics are subject to variation.

● Quality variation which is not confined within the specific range, tolerance or limit, will grow to uncontrolled
magnitude and will encourage the proliferation of errors; thus producing a defective product. In a broad sense, a defect
is an undesirable characteristic of a product.
○ It is defined as a failure to conform to specifications.
○ A unit of a product, which contains one or more defects, is called a defective. Defects can be classified as
follows:
1. According to measurability:
a. Variable defect – a defect which can be measured directly by instruments giving dimensions of length, weight,
height, thickness, concentration, volume, viscosity, pH or size particles.
■ Eg. diameter or potency
b. Attribute defect – a defect which cannot be measured directly by instruments. It shows mainly the
conformance or nonconformance of the material to specifications.
■ This applies to many things that can be judged only by odor or visual examination like color, clarity,
sheen, cleanliness, smoothness, taste and presence or absence of a characteristic (usually by
comparison to standards).
2. According to seriousness or gravity:
a. Critical defect – a defect which may endanger life or property and may render the product
non-­functional.
■ Absence or warning in a label for a potent drug or disintegration time of one hour for an analgesic are
considered critical defects.
■ Eg. mislabelled product
b. Major defect – a defect which may affect the function of the object and therefore, may render the product
useless.
■ The presence of a crack in a bottle is a major defect.
c. Minor defect – a defect which does not endanger life nor will it affect the function but nevertheless remains a
defect since it is outside the prescribed limits.
■ An example of a minor defect is the slight deviation of the color of the label from the color standards.
■ Eg. misaligned labels
3. According to nature:
a. Ocular defect – a defect that is visible, e.g., foreign particulate contamination.
b. Internal defect – a defect which is not seen although present, e.g., a subpotent drug product.
c. Performance defect – a defect in function
■ e.g., a suppository that does not melt at body temperature (may be major like glycerin or critical accdg
to the drug) and an enteric-coated tablet that disintegrates in the stomach.

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 ● Difference of defect and defective:
○ Defect → any undesirable characteristic in a product
○ Defective → product/unit with a defect
■ You can have a defective product with many defects

● The manufacture of a cosmetic or drug product frequently involves a series of simple to complex steps.
● The risk of errors increases as the number of materials used in the formulation becomes larger, and the
manufacturing processes become more complex. Errors may be due to chance or assignable causes such as:
materials, machines, methods and men.

Sources of variation:
1. Materials
a. Variation between suppliers of same substance.
b. Variation between batches from same supplier.
c. Variation within a batch.
2. Machines
a. Variation of equipment for the same process.
b. Difference in adjustment of equipment.
c. Aging and improper care.
3. Methods
a. Inexact procedures.
b. Inadequate procedures.
c. Negligence by chance.
4. Men
a. Improper working conditions.
b. Inadequate training, and understanding.
c. Dishonesty, fatigue and carelessness.

QUALITY CONTROL
● Establishes, validates, and implements all quality control procedures
● Evaluates, maintains, and stores reference standards for substances
● Ensures correct labeling of containers of materials and products
● Ensures stability of active pharmaceutical ingredients and products is monitored
● Helps investigate complaints relating to product quality
● Participates in environment monitoring

● Part of GMP
● Do we need QC/QA to produce a product? NO!
○ Before, you can get an LTO even without GMP
○ You just need raw materials, personnel, etc

ORGANIZATION OF QUALITY CONTROL

● Each pharmaceutical or cosmetic company has an organizational structure which differ somewhat from those if other
companies in scope and responsibilities. Figure 3 shows a typical organization within the quality control department.

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 Figure 3. A quality control organizational chart.

Materials Inspection Section

● Inspectors are alert individuals who had experience and who are familiar with the physical characteristics of the
materials they sample and are well versed in sampling techniques. The functions of this section are:
1. To sample and examine all raw materials received.
2. To sample and conduct physical tests on:
a. All shipments of packaging materials
b. All manufacturing, filling and packaging operations
3. To maintain periodic examination on the quality of inventories throughout all phases of storage, shipping
and distribution.
4. To perform an audit which is independent of the work done by production personnel

● In many organizations, the QC personnel may be assigned to perform several functions:

○ Inspectors are ideally alert, experienced, well-versed with the physical characteristics of the materials, and know
the sampling techniques.
● Inspection stations are placed in the area of operation, viz., warehouse, manufacturing and packaging areas.

Analytical Laboratory
● The analytical laboratory should be in an accessible area and protected from noise and vibration common to
manufacturing operations.
● It involves the performance of physical and chemical analyses of raw materials and finished goods.
● In order to perform physical and chemical analysis, the analysts should know the usual gravimetric and volumetric
analysis.
○ Furthermore, they should be skillful in handling instruments for ultraviolet and infrared spectrophotometry,
non‐aqueous titrimetry, autoanalysis, polarography, x-­ray diffraction, x­‐ray fluorescence,
spectrophotofluorimetry, radioactive tracer techniques and chromatography, viz.: column, gas, paper, thin layer
and high performance liquid chromatography.

Biological Testing Laboratory

● The staff in a biological testing laboratory should be well-trained and experienced in both simple and complex
microbiological procedures and biological interactions. They should possess a high degree of skill and judgment in
order to perform the job.
● A veterinarian is recommended to supervise the care and maintenance of the various species of animals used in the
tests. The functions of this laboratory are:
1. To perform and evaluate microbiological and pharmacological assays, sterility, pyrogen and bacteriological
tests, irritation, safety or acute toxicity tests.
2. To conduct environmental monitoring.
● Sterile conditions should be provided for areas where biological tests are conducted.
● Noise should be precluded from areas where animals are used.
● An animal house should be maintained as a separate unit from the main laboratory, if necessary.

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Microbiological Tests
1. Antimicrobial Effectiveness Testing
● This test is to demonstrate the effectiveness of antimicrobial protection. Added antimicrobial preservatives must be
declared on the label. Antimicrobial preservatives are substances added to nonsterile dosage forms to protect them
from microbiological growth or from microorganisms that are introduced inadvertently during or subsequent to the
manufacturing process. In the case of sterile articles packaged in multiple-­‐dose containers, antimicrobial
preservatives are added to inhibit the growth of microorganisms that may be introduced from repeatedly
withdrawing individual doses.
● Test organisms include Candida albicans, Aspergillus niger, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus
aureus. All media used in the test must be tested for growth promotion: Soybean-­‐ Casein Digest Broth or Agar for E.
coli, P. aeruginosa, and S. aureus, and Saboraud Dextrose Agar or Broth for C. albicans and A. niger.
● To determine the efficacy of antimicrobial preservatives added in the formulation
● Test organisms: C. albicans, A. niger, P. aeruginosa, E. coli, S. aureus
● Media: Soybean-casein digest broth or agad, Sadbouraud dextrose agar/broth for fungi

Answer: YES
● You need to perform because the effectiveness of a preservative system is formulation-specific.
● The preservative may or may not be effective.
● There could be some components in the other formulation that may interact rendering it to be less effective.

2. Microbial Limit Test

● This test is for the estimation of the number of viable aerobic microorganisms present and for freedom from designated
microbial species in pharmaceutical articles of all kinds, from raw materials to the finished forms.
● Test organisms are Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella. Culture media that can
be used are pH 7.2 Phosphate Buffer, Fluid Soybean–Casein Digest Medium, or Fluid Lactose Medium to name a few.
● Estimation of the number of viable aerobic microorganisms and absence of designated microbial specials
● Test organisms: S. aureus, E. coli, P. aeruginosa, Salmonella
● Media: in pH 7.2 phosphate bugger, Fluid soybean-casein digest medium, Fluid lactose medium

Answer: NON-STERILE PRODUCTS

● Microbial limit: certain limit of microorganisms that would be tested
○ Pwedeng may microorganism basta wag mag-exceed sa limit
● For sterile products, dapat WALA (they are for sterility testing)
○ Because sterile products should not have any microorganisms

3. Sterility Tests
● This test is applied to substances, preparations, or articles which, according to the Pharmacopeia, are required to be
sterile. However, a satisfactory result only indicates that no contaminating microorganism has been found in the
sample examined under the conditions of the test.
● This test may be carried out using the techniques of Membrane Filtration or by Direct Inoculation of the Culture Medium
with the product to be examined.
○ For membrane filtration technique, use membrane filters having a nominal pore size not greater than 0.45 μm,
in which the effectiveness to retain microorganisms has been established. Cellulose nitrate filters are used for
aqueous, oily, and weakly alcoholic solutions; and cellulose acetate filters are used for strongly alcoholic
solutions.
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 ○ Specially adapted filters may be needed for certain products.
○ For direct inoculation of the culture medium technique, the preparation to be examined is directly inoculated
into the culture medium so that the volume of the product is not more than 10% of the volume of the medium,
unless otherwise prescribed.
○ If the product to be examined has antimicrobial activity, carry out the test after neutralizing this with suitable
neutralizing substance or by dilution in a sufficient quantity of culture medium. Fluid Thioglycollate Medium
is primarily intended for the culture of anaerobic bacteria. However, it will also detect aerobic bacteria.
Soybean-­‐Casein Digest Medium is suitable for the culture of both fungi and aerobic bacteria.
● Determines whether a pharmacopoeial article purporting to be sterile complies with the requirements.
● Two methods: membrane filtration and direct inoculation/direct transfer method

ANSWER: ALL OF THE ABOVE

● Terminal sterilization: sterile product pero sa end nag-sterilize
○ Raw materials or process pwedeng hindi sterile
○ Kahit we performed terminal sterilization, it will not be identified as STERILE UNLESS TESTED
● 0.45 microns: most bacteria are 0.5 microns
○ Filters can catch the microorganism
● Cephalosporins and Penicillins: beta-lactam antibiotics
○ It should be inactivated by beta-lactamase

Biological Tests
1. Antibiotics-­‐Microbial Assay
● The activity (potency) of antibiotics may be demonstrated under suitable conditions by their inhibitory effect on
microorganisms. A reduction in antimicrobial activity also will reveal subtle changes not demonstrable by chemical
methods.
● Two general methods are employed, the cylinder-­‐plate or ‘‘plate’’ assay and the turbidimetric or ‘‘tube’’ assay.
○ The first depends upon diffusion of the antibiotic from a vertical cylinder through a solidified agar layer in a
petri dish or plate to an extent such that growth of the added microorganism is prevented entirely in a circular
area or ‘‘zone’’ around the cylinder containing a solution of the antibiotic.
○ The turbidimetric method depends upon the inhibition of growth of a microbial culture in a uniform solution
of the antibiotic in a fluid medium that is favorable to its rapid growth in the absence of the antibiotic.
● Determines potency of antibiotics
● Two methods: (1) cylinder plate or plate and (2) turbidimetric or tube

2. Bacterial Endotoxins Test

● The Bacterial Endotoxins Test (BET) is a test to detect or quantify endotoxins from Gram-­‐negative bacteria
using amoebocyte lysate from the horseshoe crab (Limulus polyphemus or Tachypleus tridentatus).
● There are three techniques for this test: the gel-­‐clot technique, which is based on gel formation; the turbidimetric

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 technique, based on the development of turbidity after cleavage of an endogenous substrate; and the chromogenic
technique, based on the development of color after cleavage of a synthetic peptide-­‐chromogen complex.
● Proceed by any of the three techniques for the test. In the event of doubt or dispute, the final decision is made
based upon the gel-­‐clot limit test unless otherwise indicated in the mono-­‐ graph for the product being tested.
The test is carried out in a manner that avoids endotoxin contamination.
● Detects and quantifies bacterial endotoxins from gram (-) bacteria
○ Currently used as a substitute for pyrogen testing
● Uses Limulus amebocyte lysate (LAL) from horseshoe crab
● Two types: (1) gel clot technique and(2) photometric technique – turbidimetric and chromogenic

ANSWER: ALL OF THE ABOVE

● Endotoxins: generated from gram-negative bacteria
● Substitute for pyrogen testing: endotoxins are usually responsible for pyrogenicity
○ Pyrogen testing: animal-testing (rabbits)
○ Nowadays, we are shunning away from animal testing (especially European countries)

3. Biological Reactivity Tests, In Vitro

● These tests are designed to determine the biological reactivity of mammalian cell cultures following contact with the
elastomeric plastics and other polymeric materials with direct or indirect patient contact or of specific extracts
prepared from the materials under test.
● Three tests are described (i.e., the Agar Diffusion Test, the Direct Contact Test, and the Elution Test).
a. Agar Diffusion Test
- This test is designed for elastomeric closures in a variety of shapes.
- The agar layer acts as a cushion to protect the cells from mechanical damage while allowing
the diffusion of leachable chemicals from the polymeric specimens.
b. Direct Contact Test
- This test is designed for materials in a variety of shapes.
- The procedure allows for simultaneous extraction and testing of leachable chemicals from the
specimen with a serum-supplemented medium.
- The procedure is not appropriate for very low-­or high-­density materials that could cause
mechanical damage to the cells.
c. Elution Test
- This test is designed for the evaluation of extracts of polymeric materials.
- The procedure allows for the extraction of the specimens at physiological or nonphysiological
temperatures for varying time intervals.
- It is appropriate for high-­‐density materials and for dose-­‐response evaluations.

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4. Biological Reactivity Tests, In Vivo
● The following tests are designed to determine the biological response of animals to elastomerics, plastics, and other
polymeric material with direct or indirect patient contact, or by the injection of specific extracts prepared from the
material under test.
● Three tests are described.
○ The Systemic Injection Test and the Intracutaneous Test are used for elastomeric materials, especially to
elastomeric closures for which the appropriate Biological Reactivity Tests, In Vitro have indicated significant
biological reactivity. These two tests are used for plastics and other polymers
○ in addition to a third test, the Implantation Test, to test the suitability of these materials intended for use in
fabricating containers and accessories thereto, for use in parenteral preparations, and for use in medical
devices, implants, and other systems.
● The systemic injection test and the intracutaneous test are designed to determine the systemic and local,
respectively, biological responses of animals to plastics and other polymers by the single-­‐dose injection of specific
extracts prepared from a sample. The implantation test is designed to evaluate the reaction of living tissue to the
plastic and other polymers by the implantation of the sample itself into animal tissue.
a. Systemic Injection Test
■ This test is designed to evaluate systemic responses to the extracts of materials under test following
injection into mice.
b. Intracutaneous Test
■ This test is designed to evaluate local responses to the extracts of materials under test following
intracutaneous injection into rabbits.
c. Implantation Test
■ This test is designed for the evaluation of plastic materials and other polymeric materials in direct
contact with living tissue.

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ANSWER: IN VIVO TEST SHOULD BE PERFORMED WITH POSITIVE RESULT IN THE IN VITRO TEST
● Higher test: in-vivo
○ In vitro yung unang ginagawa
○ If it’s a choice between in vivo and in vitro, in vitro is done first
● We do in vivo test when we get positive in the in-vitro
○ In vitro is like a preliminary step
○ In in vivo, it is more defining
○ We do in vivo if positive sa toxicity, etc
● Most of the drugs, we have in vitro tests already

5. Pyrogen Test
● This test is designed to limit to an acceptable level the risks of febrile reaction in the patient to the administration, by
injection, of the product concerned.
● The test involves measuring the rise in temperature of rabbits following the intravenous injection of a test solution
and is designed for products that can be tolerated by the test rabbit in a dose not to exceed 10 mL per Kg injected IV
within a period of not more than 10 minutes.
● If no rabbit shows an individual rise in temperature of 0.5o or more above its respective control temperature, the
product meets the requirements for the absence of pyrogens.
● If any rabbit shows an individual temperature rise of 0.5o or more, continue the test using five other rabbits.
● If not more than three of the eight rabbits show individual rises in temperature of 0.5o or more and if the sum of the
eight individual maximum temperature rises does not exceed 3.3o, the material under examination meets the
requirements for the absence of pyrogens.
● Designed to limit to an acceptable level the risks of febrile reaction in the patient upon administration by injection of
the product concerned.
● Designed or products that can be tolerated by the test rabbit in a dose not to exceed 10mL per kg IV in a period of NMT
10 mins
○ Result:
■ No (0) rabbit with rise of 0.5C or more → no pyrogen
■ Any rabbit with rise of 0.5C or more → use 5 more rabbits
■ 2nd test: NMT 3 out of 8 rabbits with rise of 0.5C or more and if the sum of the 8 maximum
temperature increase does not exceed 3.3C → no pyrogen

ANSWER: PROCEED TO THE NEXT LEVEL SAMPLING

● Add another 5 rabbits

Specifications and Analytical Development

● This section should have firm background not only in the principles of quality control and analytical procedures but
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 also in manufacturing, research, product development and in statistics in order to perform the following functions:
1. To coordinate with research, product development, production, sales and management towards improvement of a
product.
1. To establish specifications for raw and packaging materials.
2. To validate existing and tentative procedures of testing.
3. To develop new assay methods for in-­‐house use.
4. To develop and improve specifications for quality characteristics of the final product being manufactured.

Quality Coordination Office

● This section should be accessible to all manufacturing and packaging operations since documentation is its main
responsibility. The functions of this section are:
1. To maintain and store records that represents the history of the batch from start to finish. These records include the
batch and master formula records, raw material analytical records, printed and packaging material inspection
reports and retention files.
2. To be able to furnish data that will aid in analyzing product performance in the market. These documents are the
stability studies and returned goods reports.
3. To investigate customer complaints or inquiries on product quality and to forward the results of the investigations in
the form of technical reports to the sales organization.
4. To call the attention of the appropriate development group any aspect that provides a basis for improvement of a
product for consideration and action.
5. To provide data that give specific and legal status, i.e., data generated from the use of recognized standard
compendia. This is essentially a function of the distribution section or warehouse.
6. To maintain and develop SOP’s.

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 INSPECTION AND SAMPLING

● Acceptance is a basic quality function of deciding whether the product conforms to specifications.
● To arrive at a decision, the primary step is inspection. Inspection is the process of measuring, examining,
testing, or otherwise comparing the unit of product with the requirements.
● Unit of product is the unit inspected to determine its classification as conforming or nonconforming or
to count the number of nonconformities.
● It may be a single article, a pair, a set, a length, an area, an operation, a volume, a component of an end
product, or the end product itself.
● The unit of product may or may not be the same as the unit of purchase, supply, production, or shipment.

● Acceptance inspection is a necessary part of manufacturing and may be applied to incoming materials,
to partially finished product at various intermediate stages of manufacturing process (in-process
inspection), and to the final product.
● Acceptance may also be carried out by the purchaser of the manufactured product. Inspection consists
of several steps:
1. interpretation of the specification;
2. measurement of the product;
3. comparison of the product with specification;
4. judgment as to conformance;
5. disposition of the product; and
6. recording of the data obtained.

● Sometimes, the process is not sequential.

● Inspection is a preliminary step (hindi diretsong sampling na agad)
○ We inspect the label, properly sealed, the difference in color, etc

● Inspectors who take samples should receive initial and ongoing regular training in the disciplines
relevant to correct sampling.
● The training should include
○ (1) sampling plans,
○ (2) written sampling procedures,
○ (3) the techniques and equipment for sampling,
○ (4) the risks of cross-contamination,
○ (5) the precautions to be taken with regard to unstable and/or sterile substances,
○ (6) the importance of considering the visual appearance of materials, container and labels, and
○ (7) the importance of recording any unexpected or unusual circumstances.

INSPECTION METHODS
1. 100% inspection can be a formidable task unless the 100% inspection is performed with automatic test
equipment.
● In addition, it is not always successful, particularly when a large number of items have one or
more characteristics that are marginal dimensionally, in appearance or in performance (close to
or concentrated about a tolerance or limit of appearance or performance).
● Under these conditions, sorting by manual or automatic methods is likely to classify some
conforming items as nonconforming, and vice versa.
● In addition, 100% testing by manual, visual or automatic methods can be unsatisfactory.
● It can sometimes degenerate into superficial 100% inspection when, in fact, sufficient money,
time and staff are not available. 100% inspection is not viable if the inspection method
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 necessitates destructive testing.
● We inspect all the units (if the unit is 1000, you inspect 1000)
● 100% inspection can be done on a small-scale only (eg. pharmacists in the hospital, community,
etc)
● Disadvantages:
○ (a) prohibitive cost → malulugi yung company
○ (b) prone to error → especially if manual; less prone to error if automated
○ (c) not an assurance
○ (d) not applicable when doing destructive test
○ (e) applicable only for parenteral preparations (eg. injectables; critical nature of the
product) → usually visual or automated inspection (no protein particles, discoloration,
etc)
■ Sterile products: not just parenteral (meron ding ophthalmic, irrigation, etc)

2. Sampling inspection
● Sampling inspection is an important operation in which only a small fraction of a batch is taken.
Valid conclusions on the whole cannot be based on tests which have been carried out on
non-representative samples.
● Correct sampling is thus as essential part of a system of Quality Assurance.
● In sampling, one must consider the laws of probability.
● There are certain risks involved; namely, the risk of error.
● A producer’s risk (α) is the probability of rejecting a good batch, whereas a consumer’s risks (β)
is the probability of accepting a bad batch.
● Representative units of the batch are inspected
○ Should be representative (randomized)
● Considers the laws of probability, and involves the risk of errors:
○ a. producer’s risk → type 1 error or alpha error
■ Because you just did sampling, baka ma-reject yung buong batch which is good
naman
■ Nawalan yung producer. Hence, this is the producer’s risk.
○ b. consumer’s risk
■ Consumer’s risk by accepting a bad batch.
● Gives better quality assurance than 100% inspection
● Requires N (population/batch), n (sample size), and Ac/c (acceptance number)
○ N: the bigger the population, the more the sample size
■ Eg. N = 1000, n = 50, Ac/c = 5
● Out of 1000, you will randomly secure 50 for testing and out of the 50,
dapat equal or less than 5 lang yung may defect

● Sampling inspection is used in lieu of 100% inspection because of the disadvantages stated
above.
● It is common knowledge that on may types of inspection, even several 100% inspections will not
eliminate all of the defective product from a stream of product, a portion of which is defective.
● The best protection is, of course having the product made right in the first place.

● Sample (n) is a portion of a material collected according to a defined sampling procedure.

● The size of any sample should be sufficient to allow all anticipated test procedures to be carried
out, including all repetitions and retention samples.
● If the quantity of material available is not sufficient for the intended analyses and for the
retention samples, the inspector should record that the sampled material is the available
sample, and the evaluation of the results should take account of the limitations that arise from
the insufficient sample size.
● Sample also pertains to one or more units of product drawn from a lot or batch, the units of the
sample being selected at random without regard to their quality.
● The number of units of product in the sample is the sample size.
● When appropriate, the number of units in the sample shall be selected in proportion to the size
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 of sublots or sub-batches, or parts of the lot or batch, identified by some rational criterion. In so
doing, the units from each part of the lot or batch shall be selected at random.
● A random sample is a sample chosen in such a manner that one object has a good chance of
being selected as another.
● It is a sample in which the different fractions of the material have an equal probability of being
represented.
● Samples may be drawn after all the units comprising the lot or batch have been produced, or
samples may be drawn during production of the lot or batch.

● Inspection by variables is the inspection by measuring the magnitude of a characteristic of an item.

● Variables = measurable
● Eg. Tablet weight, fill volume, tablet diameter, etc
● Inspection by attributes is inspection whereby either the unit of product is classified simply as
conforming or nonconforming, or the number of nonconformities in the unit of products is counted, with
respect to a given requirement or set of requirements.
● Comparing to standard (no in-betweens, values, specifications)
● Eg. Color, odor, etc

The following to definitions are particularly important in applying the ANSI/ASQ Z1.4-2008 standard.
● DEFECT: A departure of a quality characteristic from its intended level or state that occurs with a severity
sufficient to cause an associated product or service not to satisfy intended normal, or foreseeable, usage
requirements
● Did not meet the intended usage requirement
● NONCONFORMITY: A departure of a quality characteristic from its intended level or state that occurs
with severity sufficient to cause an associated product or service not to meet a specification
requirement.
● Here, we have specification requirements (unlike in defect)
● The extent of nonconformance of product shall be expressed either in terms of percent nonconforming or
in terms of non- conformities per hundred units.

● The percent nonconforming of any given quantity of units of product is one hundred times the number of
nonconforming units divided by the total number of units of product, i.e.:

● nonconforming units → more like defective units (pero dapat NONCONFORMING meaning MAY
SPECIFICATIONS)
● units inspected → sample size

● The number of nonconformities per hundred units of any given quantity of units of product is one
hundred times the number of nonconformities contained therein (one or more nonconformities being
possible in any unit of product) divided by the total number of units of product, i.e.:

● nonconformities → defects (may have more than 1 nonconformity in 1 unit)

● units inspected → sample size

*OWN UNDERSTANDING: Sa per hundred units, pwedeng mas malaki yung value ni numerator kaysa kay
denominator since one non-conforming product or one unit can have multiple defects or non-conformities.

● It is assumed that nonconformities occur randomly and with statistical independence within and
between units.

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SAMPLING PLAN
● A sampling plan indicates the number of units of product from each lot or batch which are to be
inspected (sample size or series of sample sizes) and the criteria for determining the acceptability of the
lot or batch (acceptance and rejection numbers).

● The term lot or batch shall mean “inspection lot” or “inspection batch,” i.e., a collection of units of
product from which a sample is to be drawn and inspected to determine conformance with the
acceptability criteria and may differ from a collection of units designated as a lot or batch for other
purposes (e.g., production, shipment, etc.). The lot or batch size is the number of units of product in a lot
or batch.

● An individual sampling plan is a specific plan that states the sample size or sizes to be used, and the
associated acceptance criteria, while a sampling scheme is a combination of sampling plans with
switching rules and possibly a provision for discontinuance of inspection. Sampling plans are applied to
inspection of the following:
1. end items
2. components and raw materials
3. operations
4. materials in process
5. supplies in storage
6. maintenance operations
7. data or records
8. administrative procedures

ACCEPTANCE QUALITY LIMIT (AQL)

● The AQL is the quality level that is the worst tolerable process average (maximum number of
non-conformities) when a continuing series of lots is submitted for acceptance sampling. It is only
applied when an acceptance sampling scheme with rules for switching between normal, tightened, and
reduced inspection and discontinuance of sampling inspection is used.
○ Not very important product = higher AQL
○ Critical parameter = lower AQL (less number of non-conforming units)
○ AQL below 10 = number of non-conforming units
○ AQL equal or higher than 10 = non-conformities
● These rules are designed to encourage suppliers to have process averages consistently better than the
AQL. If suppliers fail to do so, there is a high probability of being switched from normal inspection to
tightened inspection where lot acceptance becomes more difficult.
● Once on tightened inspection, unless corrective action is taken to improve product quality, it is very
likely that the rule requiring discontinuance of sampling inspection will be invoked.

● The AQL to be used will be designated in the contract or by the responsible authority.
● Different AQLs may be designated for groups of nonconformities considered collectively, or for individual
nonconformities.
● An AQL for a group of nonconformities may be designated in addition to AQLs for individual
nonconformities, or subgroups, within that group. AQL values of 10.0 or less may be expressed either in
percent nonconforming or in nonconformities per hundred units; those over 10.0 shall be expressed in
nonconformities per hundred units only.

ACCEPTANCE AND NON-ACCEPTANCE

● Acceptability of a lot or batch will be determined using a sampling plan or plans associated with the
designated AQL or AQLs.
● A lot is acceptable means simply that sample results satisfy the standard’s acceptance criteria. It is not
intended to provide information about lot quality.
● The purpose of the standard is, through the economic and psychological pressure of lot non-acceptance,
to induce a supplier to maintain a process average at least as good as the specified AQL while at the
same time providing an upper limit on the consideration of the consumer’s risk of accepting occasional
poor lots.

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 ● The standard is not intended as a procedure for estimating lot quality or for segregating lots.

● In acceptance sampling, the words “to reject” generally are used to mean “to not accept” without direct
implication of product usability.
● Lots which are “rejected” may be scrapped, sorted (with or without nonconforming units being replaced),
reworked, re-evaluated against more specific usability criteria, held for additional information, etc.
● Since the common language usage of “reject” often results in an inference of unsafe or unusable
product, it is recommended that “not accept” be understood rather than “reject” in the use of this
standard.
● The word “non-acceptance” is used here for “rejection” when it refers to the result of following the
procedure.
● Forms of the word “reject” are retained when they refer to actions the customer may take, as in “rejection
number.”

● The right is reserved to reject any unit of product found nonconforming during inspection whether that
unit of product forms a part of a sample or not, and whether the lot or batch as a whole is accepted or
rejected.
● Rejected units may be repaired or corrected and resubmitted for inspection with the approval of, and in
the manner specified by, the responsible authority.

SUBMISSION AND RESUBMISSION OF PRODUCT

● Lots or batches found unacceptable shall be resubmitted for reinspection only after all units are
re-examined or re- \tested and all nonconforming units are removed or nonconformities corrected.
● The responsible authority shall determine whether normal or tightened inspection shall be used on
reinspection and whether reinspection shall include all types or classes of nonconformities or only the
particular types or classes of nonconformities which caused initial rejection.

INSPECTION LEVELS
● The inspection level determines the relationship between the lot or batch size and the sample size.
● The inspection level to be used for any particular requirement will be prescribed by the responsible
authority.
● Three inspection levels: I, II and III are given in Table I for general use. Unless otherwise specified,
Inspection Level II will be used.
● However, Inspection Level I may be specified when less discrimination is needed, or Level III may be
specified for greater discrimination.
● Four additional special levels: S-1, S-2, S-3, and S-4, are given in the same table and may be used where
relatively small sample sizes are necessary and large sampling risks can or must be tolerated.

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SWITCHING PROCEDURE FOR NORMAL, TIGHTENED, AND REDUCED INSPECTION

Figure 1. Switching Rules for ANSI Z1.4 System

● Normal scheme: relatively reliable supplier

● Tightened inspection: requires more number of samples in the testing or evaluation
○ Normal → tightened: converted when 2 out of 5 batches fail
○ Tightened → normal: converted when 5 consecutive batches are accepted
■ Tightened and 5 consecutive batches not accepted → discontinue
○ Normal → reduced: 10 lots accepted, etc
● Normal to reduced sampling: less sample, less man hour, fewer resources
○ Reduced sampling = increased risk
○ Reduced to normal can also happen

● Normal inspection will be used at the start of inspection unless otherwise directed by the responsible
authority. When normal inspection is in effect, tightened inspection shall be instituted when 2 out of 5 or
fewer consecutive lots or batches have been non-acceptable on original inspection (i.e., ignoring
resubmitted lots or batches for this procedure).

● When tightened inspection is in effect, normal inspection shall be instituted when 5 consecutive lots or
batches have been considered acceptable on original inspection.
● When normal inspection is in effect, reduced inspection shall be instituted providing that all of the
following conditions are satisfied.
1. The preceding 10 lots or batches (or more, as indicated by the note to Table 1) have been on
normal inspection, and all have been accepted on original inspection; and
2. The total number of nonconforming units (or nonconformities) in the samples from the
preceding 10 lots or batches is equal to or less than the applicable limit number given in Table 1.
If double or multiple sampling is in use, all samples inspected should be included, not “first”
samples only; and
3. Production is at a steady rate; and
4. Reduced inspection is considered desirable by the responsible authority.

● When reduced inspection is in effect, normal inspection shall be instituted if any of the following occur
on original inspection:
1. A lot or batch is rejected; or
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 2. A lot or batch is considered acceptable under special procedure for reduced inspection in which
the sampling procedure may terminate without making a decision
3. Production becomes irregular or delayed; or
4. Other conditions warrant that normal inspection shall be instituted.

● If the cumulative number of lots not accepted in a sequence of consecutive lots on tightened inspection
reaches 5, the acceptance procedures of this standard shall be discontinued.
● Inspection under the provisions of this standard shall not be resumed until corrective action has been
taken.
● Tightened inspection shall then be used.

Table 1. Limit Numbers for Reduced Inspection

● Sample sizes are designated by code letters. Table 2 shall be used to find the applicable code letter for
the particular lot or batch size and the prescribed inspection level.

● The AQL and the code letter shall be used to obtain the sampling plan from single, double, or multiple
sampling plan.
● When no sampling plan is available for a given combination of AQL and code letter, the tables direct the
user to a different letter.
● The sample size to be used is given by the new code letter, not by the original letter.

● Three types of sampling plans: Single, Double and Multiple.

● When several types of plans are available for a given AQL and code letter, any one may be used.
● A decision as to type of plan, either single, double, or multiple, when available for a given AQL and code
letter, will usually be based upon the comparison between the administrative difficulty and the average
sample sizes of the available plans.
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● The average sample size of multiple plans is less than for double and both are always less than a single
sample size.
● Usually, the administrative difficulty for single sampling and the cost per unit of the sample are less
than for double or multiple.

Table 2. Sample size code letters

● Lot or batch size = population

● In general, we use general inspection levels (specifically level II)
● General level I: relatively confident to the supplier
● General level III: parallel to title inspection: higher sample size code letter (reasons to doubt the quality
of the supplier)
● We use special inspection levels when:
1. We can tolerate large sampling risks or error
○ Lower letter = lower sample size
2. In special inspection, we require fewer samples unlike in general inspection
○ Eg. very expensive materials (esp if destructive testing)

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 ● This inspection method is decided BEFORE conducting the test (defined at the start)

DETERMINATION OF ACCEPTABILITY
1. To determine the acceptability of a lot or batch under Nonconformities per Hundred Units inspection, the
procedure specified for Percent Nonconforming inspection shall be used, except that the word
“nonconformities” shall be substituted for “nonconforming units.
2. To determine the acceptability of a lot or batch under percent nonconforming inspection, the applicable
sampling plan shall be used:

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a. Single Sampling Plan: The number of sample units inspected shall be equal to the sample size
given by the plan.
● If the number of nonconforming units found in the sample is equal to or less than the
acceptance number, the lot or batch shall be considered acceptable.
● If the number of nonconforming units is equal to or greater than the rejection number,
the lot or batch shall be considered not acceptable.

Figure 2. Schematic operation of single sampling plan.

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b. Double Sample Plan: The number of sample units first inspected shall be equal to the first
sample size given by the plan.
● If the number of nonconforming units found in the first sample is equal to or less than
the first acceptable number, the lot or batch shall be considered acceptable.
● If the number of nonconforming units found in the first sample is equal to or greater
than the first rejection number, the lot or batch shall be considered not acceptable.
● If the number of nonconforming units found in the first sample is between the first
acceptance and rejection numbers, a second sample of the size given by the plan shall
be inspected.
● The number of nonconforming units found in the first and second samples shall be
accumulated.
● If the cumulative number of nonconforming units is equal to or less than the second
acceptance number, the lot or batch shall be considered acceptable.
● If the cumulative number of nonconforming units is equal to or greater than the second
rejection number, the lot or batch shall be considered not acceptable.

Figure 3. Schematic operation of double sample plan.

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● Multiple Sample Plan: Under multiple sampling, the procedure shall be similar to that specified in
Double Sampling Plan, except that the number of successive samples required to reach a decision might
be more than two.

Figure 4. Schematic operation of multiple sampling method.

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 Table 3. Single sampling plans for normal inspection (Master table)

Table 4. Single sampling plans for tightened inspection (Master table)

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 Table 5. Single sampling plans for reduced inspection (Master table)

SAMPLE PREPARATION
1. Crude drugs

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● CRUDE → not purified or semi-purified only
○ eg. plant extracts, animal extracts (usually consist of mixtures not qualified/identified
composition)
○ can come in 2 forms: bulk (drums/sacks) or packed (sachets, etc)
a. 2 types: gross sample and lab sample
i. Gross sample: number of containers (50 drums need to open or 100 bundles of labels)
1. Greater than 50 units: 10% of rounded up value to the nearest 1-s for a number of
packages
a. eg. 73 packages = 80 rounded up
i. 10% of 80 = 8 packages
ii. Lab sample: actual material
1. In 8 packages to be opened, how much material is needed?
2. crude drug is heterogenous (not uniform material); hence, we need to get from
the top, bottom, and up and pull the sample

A. Sampling of material in bulk

● If initial inspection indicates that the batch is uniform, take samples as follows.
● When a batch consists of five containers or packaging units, take a sample from each one. From
a batch of 6–50 units, take a sample from five. In the case of batches of over 50 units, sample
10%, rounding up the number of units to the nearest multiple of 10.
● For example, a batch of 51 units would be sampled as for 60 — i.e. take samples from six
packages.

● From each container or package selected, take three original samples, taking care to avoid
fragmentation.
● Samples should be taken from the top, middle and bottom of the container.
● In the case of sacks and packages, the three samples should be taken by hand, the first from a
depth of not less than 10 cm from the top and the second and third from the middle and bottom
after cutting into the side of the package.
● Samples of seeds should be withdrawn with a grain probe.
● Material in boxes should first be sampled from the upper layer; then approximately half of the
contents should be removed and a second sample taken.
● Finally after further removal of material, another sample should be taken from the bottom.
Samples should be as uniform as possible in mass.
● The three original samples should then be combined into a pooled sample which should be
mixed carefully.

● The average sample is obtained by quartering.

● Form the pooled sample, adequately mixed, into an even and square-shaped heap, and divide it
diagonally into four equal parts. Take two diagonally opposite parts and mix carefully. Repeat the
process as necessary until the required quantity, to within ± 10%, is obtained (100– 200 g for
Yen ♡ | 15
 flowers and up to 10 kg for certain roots).
● Any remaining material should be returned to the batch.

● Using the same quartering procedure, divide the average sample into four final samples, taking
care that each portion is representative of the bulk material. The final samples are tested for the
following characteristics:
- degree of fragmentation (sieve test);

- identity and level of impurities;

- moisture and ash content;

- level of active ingredients, where possible.

● A portion of each final sample should be retained to serve as reference material, which may also
be used for re-test purposes, if necessary.

B. Sampling of material in retail packages

● From each wholesale container (boxes, cartons, etc.) selected for sampling, take at random two
consumer packages.
● From small batches (1–5 boxes), take 10 consumer packages.
● Prepare the pooled sample by mixing the contents of the selected consumer packages and
proceed as described above to obtain the final sample.

2. Purified raw material/Starting materials

● “alam na natin kung ano sila” → they're already characterizied
● n plan = square root of N + 1
○ eg. N = 50 containers
● square root of 50 + 1 = 8.07 or 9 (round up always)
○ always one more sample than less sample (partial is not allowed)

● Test sample: amount for one complete analysis based on tests outlined in the monograph
○ one complete analysis based on the monograph or the specs
○ ID test: 1.0 g (qualitative) x 1 = 1.0g
■ Required for all containers
○ Limit test: 0.5 g (can be quali or quanti but for us, quantitative) x 1 = 0.5 g
○ Impurity test = 1.0 g (quantitative) x 2 = 2.0 g
○ Assay = 2.0 g (always quanti) x 2 = 4.0 g
■ = 7.5 g is the amount for 1 complete analysis = TEST SAMPLE
■ Lab sample = 7.5 g x 3 = 22.5
● Required to take reference sample
● Lab sample = x3
● Reference/Retention Sx = x2
○ To identify if magkaproblem sa production
● Test sx + Reference Sx = lab Sx

SOLUBILITY → qualitative
WATER → quantitative
PRIMARY AMINES AND AMMONIA → quantitative
● Composition → quanti usually
● QUALI OR QUANTI: if basis ay number, QUANTI. if color color lang, QUALI.

A. Gross sample
● All containers must be withdrawn for individual samples and identity tests must be performed.
Sampling can be done if a validated procedure has been established to ensure that no single
container of starting material will be incorrectly identified on its label and only if:
1. the starting materials are coming from a single product manufacturer or plant;
2. the starting materials are coming directly from a manufacturer or in the manufacturer's
sealed container where there is a history of reliability and regular audits of the

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 manufacturer's Quality Assurance system are conducted by the purchaser (the
manufacturer of the medicinal products or by an officially accredited body.

● This cannot be applied to:

1. starting materials supplied by intermediaries such as brokers where the source of
manufacture is unknown or not audited;
2. starting materials for use in parenteral products.

● The “n plan” can be used for general sampling but it should be used with great caution and only
when the material to be sampled is considered uniform and is supplied from a recognized
source.
● Samples can be withdrawn from any part of the container (usually from the top layer). The n plan
is based on the formula n = 1 + √𝑁, where N is the number of sampling units in the consignment.
The value of n is obtained by simple rounding.
● A minimum number of containers needs to be sampled, e.g. if N is less than or equal to 4, then
every container is sampled.
● According to this plan, original samples are taken from n sampling units selected at random and
these are subsequently placed in separate sample containers (see Appendix 1).
● The control laboratory inspects the appearance of the material and tests the identity of each
original sample according to the relevant specification.
● If the results are concordant, the original samples are combined into a final, composite sample
from which an analytical sample is prepared, the remainder being kept as a retention sample. It
is important to recognize that the “n plan” is not statistically based and should be used only as a
guiding principle. This is also referred to as square root system.

B. Test sample
● the amount of sample for one complete analysis. It is dependent on the number of tests required
in the drug monograph. The quantity needed to describe the material is no longer counted.
Identification and Solubility tests are reported on pooled sample. Quantitative tests are
performed twice.
● Laboratory sample is equal to three times the amount of sample for one complete analysis.
● Reference sample is a sample of a batch of starting material, packaging material or finished
product which is stored for the purpose of being analyzed should the need arise during the shelf
life of the batch concerned. It also includes samples from critical intermediate stages ((e.g. those
requiring analytical testing and release) or intermediates that are transported outside of the
manufacturer's control. It is two times the amount of sample for one complete analysis, or as
required by national authority.

3. In-process items
A. Gross sample is withdrawn on a time basis or as portions of batch.
B. Laboratory sample is based on GMP, in-house or pharmacopeial requirement.
● Eg. Granules
● No retention samples

4. Finished products
● The minimum size of the samples will be determined by the requirements of the analytical
procedure that will be used to test the product.
● Tests of unit dosage forms for uniformity of weight, volume or content can require a considerable
number of units, as can tests for sterility.
● Depending upon the type of material, the size of the consignment and the way in which the
material is packed, a unit to be sampled may be regarded as the transport container
● e.g. 20 packs shrink-wrapped or boxed together, rather than an individual container
● The required number of unit dosage forms is then withdrawn from any individual container in
the selected transit container.
● When sampling finished products, packaging materials may be retained for testing.
● Eg. you need 2 tabs, you get the whole carton/pack and not just blisters

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 ● Critical to keep retention sample

● In some cases it may be sufficient to limit examination of finished goods to visual inspection
only.
● If physical and chemical testing is required, however, the sampling units should consist of whole
packs.
● Individual packs should not be broken open for the purposes of sampling.

● Retention sample: a sample of a fully packaged unit from a batch of finished product. It is stored
for identification purposes.
● For example, presentation, packaging, labeling, patient information leaflet, batch number, and
expiry date should the need arise during the shelf life of the batch concerned.
● There may be exceptional circumstances where this requirement can be met without retention of
duplicate samples
○ e.g. where small amounts of a batch are packaged for different markets or in the
production of very expensive medicinal products.

● For finished products, in many instances the reference and retention samples will be presented
identically, i.e. as fully packaged units.
● In such circumstances, reference and retention samples may be regarded as interchangeable.

● Where a batch is packaged in two, or more, distinct packaging operations, at least one retention
sample should be taken from each individual packaging operation. Any proposed exception to
this should be justified to, and agreed with, the relevant competent authority.
● For parallel imported/parallel distributed products:
1. where the secondary packaging is not opened, only the packaging material used needs to
be retained, as there is no, or little, risk of product mix up
2. where the secondary packaging is opened
● for example, to replace the carton or patient information leaflet, then one
retention sample, per packaging operation, containing the product should be
taken, as there is a risk of product mix-up during the assembly process. It is
important to be able to identify quickly who is responsible in the event of a
mix-up (original manufacturer or parallel import assembler), as it would affect
the extent of any resulting recall.

5. Packaging materials
● The sampling plan for packaging materials should take account of at least the following:
1. the quantity received
2. the quality required,
3. the nature of the material (e.g. primary packaging materials and/or printed packaging
materials),
4. the production methods, and
5. the knowledge of Quality Assurance system of the packaging materials manufacturer
based on audits.
● The number of samples taken should be determined statistically and specified in a sampling
plan.

A. Gross sample is computed using the n plan. It is the number of packages to be opened for withdrawal of
samples.
B. Laboratory sample is determined using the military standard for attributes.

SAMPLING TOOLS
1. Scoops
● Small containers of solid materials may be adequately sampled using a spatula or scoop (See
Figure 5). The samples are then blended to provide a representative sample of that container. The

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 size of the scoop depends on the amount of sample to be taken. A scoopful of sample should be
taken in a single movement and transferred to the sample container. Avoid tapping the scoop to
remove pharmaceutical product, as this is likely to cause segregation of the sample.

2. Dip tubes
● Dip tubes (See Figure 6.) should be used for sampling liquid and topical products and should be made of
an inert material, such as polypropylene or stainless steel.

3. Weighted containers
● For taking samples from large tanks and storage vessels, a container in a weighted carrier can be used.
● The container is designed such that it can be opened at the required depth.
● Marks on the cord used for lowering the container can be used to determine when the correct sampling
depth has been reached. Figure 7 is an example of a typical weighted container.

4. Thieves
● Sample thieves should be used when taking samples from deep containers of solids. Typical thieves are
shown in Figure 8.

● The plug thief typically consists of a hollow tube with an inner rod that has a tip on the end to allow the
thief to enter the powder bed in the closed position (see Figure 7.i).
● The geometry of this tip can influence the sample taken; pointed tips distort the powder bed less than
blunt-tipped probes, thereby reducing sampling error.
● Some thieves have a locking device that allows the sample volume to be set to the required sample
weight, thereby reducing the weight variation in the sample population.

● A chamber thief generally consists of two concentric tubes (see Figure [Link]); the inner tube is solid except
for the chambers in which the sample is collected.
● The outer tube is hollow with openings that can be aligned with the chambers in the inner tube. A
well-designed thief will have a sharp end to minimize disruption to the powder bed.

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5. Simple bag-sampling spears
● Simple bag-sampling spears are the most commonly used instruments for taking samples from bags,
because they are relatively cheap, simple and quick.
● Sampling spears generally have a maximum external diameter of about 12 mm, but can be up to 25mm
in diameter.
● To obtain a good cross-sectional sample, the spear should be 40–45 cm in length.
● The tapered type of sampling spear penetrates bags easily. Typical spears are shown in Figure 9.

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PRACTICE EXERCISES:

Example: N = 25000
● Code Letter M
● AQL = 1.0

Code M
Sample size: 315
AQL = 1.0
Acceptance number: 7
Rejection number: 8
● Acceptance and rejection numbers differ in 1 unit only

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ANS: Proceed to 2nd sampling

ANS: Do not accept the batch

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Exercises on sampling preparation:
1. For a shipment of 100 labels, the acceptance limit is 25 nonconformities; 9 nonconformities were found
during sampling.
a. What is the batch size?
b. Give the sample size code letter.
c. What is n using the master tables?
d. Give the AQL.
e. What is Ac using the master tables?
f. What is the disposition?

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2. What is the Ac if Re is 23?
3. Solve for the batch size if n is 4 using the n plan.
4. For an AQL of 0.15, what is the maximum number of nonconformities acceptable for 10,000 pieces of
cartons?
5. Fourteen drums of Muriatic acid were received in the warehouse.
a. If the shipment has the same batch number in all drums, how many drums should be sampled?
b. If the shipment consists of 2 drums with one batch number and 12 drums with another batch
number, give the sample size for each batch.
6. In acceptance sampling under the ANSI/ASQ Z1.4-2008 standard, single sampling is to be used with
Inspection Level II, for a batch of 100,000 pieces of labels. Give the acceptance criteria for normal
sampling if the AQL is 1.5.
7. Explain how a sample size of 5 units with an AQL of 150 can have an acceptance number of 14.
8. Fifty sacks of 25 kg each of Psidium guajava folium were received for sampling. Calculate the gross
sample and gross delivery.
9. Seventy cans of Powdered Luya Rhizome were received by the warehouse. Inspection of the
containers shows that 67 had the lot number R12-04 printed on the label while 3 cans were
identified with a lot number of R15-04. How much is the gross sample?
10. Given below is the list of tests needed to measure the quality of Piperazine Citrate USP:

a. How many grams of the material are needed for one complete analysis?
b. How much is the laboratory sample?
c. How much is the retention sample?

11. One hundred sixty-four cases of glass bottles of 30mL, each containing 12 dozens, were subjected to
acceptance sampling. Determine the following:
a. gross sample
b. laboratory sample size
c. If cracks in some bottles were noted,
1. what AQL should be considered: 0.65 or 65?
2. what is the acceptance number?
3. what is the rejection number?

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