Pharmaceutical Lesson 2.

4: PQS: GOOD QUALITY CONTROL LABORATORY

Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

Quality Control Quality Assurance

OUTLINE Product approach Process approach
1. General Reactive Proactive
2. Principle Corrective Tool Preventive tools
Testing and Controlling Develop and Assuring
3. Quality Relationship: Differences between QC
Identification and Defect Defect Avoiding
and QA correction
4. Basic Principles of Good Quality Control
Laboratory Practice Basic Principle of Good Quality Control Laboratory
5. Sampling Practice
6. Testing
7. On-going Stability Programme
8. Contract Analysis

General
Quality Control is part of Good Manufacturing Practice which is
concerned with:
 sampling,
 specifications and testing, and
 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.
PERSONNEL
Principles  QC Personnel shall comply with requirements as stipulated in
 Manufacturers of TM/HS shall have a quality control systems Chapter 2 – Personnel:
which is designed to ensure that products are manufactured - Qualification and competency of QC Personnel
under adequate conditions and in accordance with - Responsibilities
procedures so as to meet established specifications, - Joint responsibility of the Heads of Production and QC
 Quality control is not confined to laboratory operations, but department
must involve in all decisions which may concern the quality of  Qualification and competency of QC personnel
the product.  Quality Control personnel shall have particular expertise
 To meet this purpose, Quality Control Department should be in products, in order
appropriate and independent o to be able to carry out identification tests and
o to detect adulteration,
Quality Relationship: Differences Between QC and o to detect the presence of fungal growth,
QA infestations, and
o to identify non-uniformity when receiving and
checking crude materials
 Competent personnel with specific expertise on natural
products should be an advantage, since crude material can be
an aggregate of an individual natural material which contain
an element of heterogeneity.
 Qualification and competency of Microbiology Analyst:
o Microbiological testing shall be performed and
supervised by an experienced person, qualified in
microbiology or equivalent.
Quality Assurance o Analyst should have basic training in microbiology
 A wide-ranging concept which covers all matters which and relevant practical experience before being
individually or collectively influence the quality of a product allowed to perform work covered by the scope of
 Appropriate infrastructure or “quality system” consists of testing
organization structure, procedures, processes and resources o Shall understand:
 The sum total of the organized arrangements to ensure  procedures for containment of
that the products are of the quality required for their intended microorganisms within the laboratory
use facility
 Quality Assurance therefore incorporates Good  In safe handling of microorganisms
Manufacturing Practice plus other factors outside the scope of  Training for Microbiology Analyst shall cover:
these Guidelines, such as product design and development o basic technique of:
 plate pouring,
 counting of colonies,
Differences between QC- QA  aseptic technique,
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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

 media preparation, o Reference substances and reference materials

 serial dilutions, and  Microbiological testing
 techniques in identification, with o Culture Media
acceptability determined using objective o Reference Culture
criteria where relevant.
 procedures for containment of
microorganisms
 safe handling of microorganisms
o interpretations of test results

 Reagents
o Types of reagents
 Directly used
 Prepared in laboratory: Chemical
substance, buffer solution, volumetric
Training solution, solvent.
 The head of Quality Control Department shall have adequate o Grade of reagent
training (such as knowledge of Good Quality Control  (purity) should be appropriate for use as
Laboratory Practice and TM/HS analysis) and practical indicated in the testing procedure
experience, which can enable the person to perform the  Analytical
functions effectively  HPLC − USP, BP, EP, JP grade,
etc
PREMISES o Label of Reagents
 The Quality Control Department shall have a designated area
with sufficient to perform any required analysis before, during
and after manufacture.
 Quality Control Laboratory/Premises shall comply with
requirements as stipulated in Chapter 3 – Premises and
Equipment.

EQUIPMENT
 Availability of QC equipment shall be based on testing
methods:
o Balances
o Measuring equipment of an appropriate range and  Preparation of reagent
precision shall be available for analytical test o Responsibility for this task should be assigned
o Glassware clearly specified in the job description of the
o Analytical instrument/equipment assigned
 For calibration and documentation regarding QC equipment o Prescribed procedures should be used which are in
refer to Chapter 3 – Premises and Equipment and Chapter 5 accordance with published pharmacopoeia or valid
– Documentation internal method/instruction
 Verification of Equipment o Records such as log-book should be kept of the
o Equipment shall be verified to determine if they are preparation and standardization of
still operating in a valid state reagent/volumetric solutions.
o Verification of equipment should be done prior to the
testing method verification
o For details, refer to Appendix 2- Verification

MATERIALS
 General Principles
o Reagent, media culture, reference of substances, o Visual inspection
materials and culture used in tests and assays – of  Delivered reagent containers should be
appropriate quality and should be accompanied by visually inspected to ensure that the seals
 the certificate of analysis, and are intact.
 the material safety data sheet, if required o Water as reagent
 Chemical testing  The appropriate grade for testing as
o Reagents described in the pharmacopoeias.

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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

 The quality of the water should be verified  A substance whose characteristics are
regularly to ensure that water meet the assigned and/or calibrated by comparison
specifications with a primary reference substance
o Storage  Preparation of Working standard
 reagent/volumetric solution should be kept in  The information shall include the
reagent bottle and put it on the shelf results of all tests and verifications
 stored under the designated storage used to establish the reference
conditions (ambient temperature, under substances and expiry date or
refrigeration, with proper dessication). retest date; signed by the
 note: responsible analyst
 flamable reagent= flamable storage  All preparation shall be performed
 poison or toxic reagent = stored in in accordance to instruction and
a locked or secured cabinet duly recorded
 Reference Substances and Reference Materia o Handling
o Reference substances are intended for use in  A person should be nominated to manage
specified chemical and physical tests, in which its reference substances and reference
properties are compared with those of the product materials.
under examination, and which possesses an  Registration of material should be maintained
adequate degree of purity in log book, at least containing information
o Reference materials are intended for calibration of :
and/or qualification of equipment, instruments or
other devices, e.g. pH buffer for pH-meter
standardization
 Reference Substance:
o Active ingredients for herbal material(s) or
preparation(s)
o Constituent with known therapeutic activities are
known, the active ingredients should be  Identification number should be:
standardized to contain a defined amount of o Marked on each vial/container
this/these constituent(s) o Quoted on the analytical worksheet when used
 e.g. : Piperine originated from Piper  Media
retrofractum extract, Apigenin originated from o Media shall be obtained from qualified supplier
Apii herbal extract o Growth promotion test should be done on each
o The reference standard may be a botanical sample prepared media
of the herbal material o Positive and Negative control should be carried out on
 If the herbal medicine is not described in a every test
recognized pharmacopoeia, a herbarium o Records such as log-book should be kept for the
sample of the flowering or fruiting top of the preparation of media (incl. expired date of media)
whole medicinal plant or part of the medicinal  Reference Culture
plant may be used for macroscopic o Reference cultures should be obtained from
identification
recognized source which have WHO International
o Primary reference substance
Biological Standards Category (status and traceable),
 A substance that is widely acknowledged
− e.g. Eschericia coli ATCC 8739, Pseudomonas
to possess the appropriate qualities within a
aeruginosa ATCC 9027
specified context, and whose assigned
o Subcultured not more than 5 generations (passages)
content is accepted without requiring
o Provided with CoA
comparison with another chemical
substance. HANDLING OF QC MATERIALS
 Note: Pharmacopoeia chemical reference  Passage of reference culture:
substances are considered to be primary
reference substances.
 In the absence of a pharmacopoeia
reference substance, a manufacturer should
establish a primary reference substance
 Active ingredients for health supplement
material(s) or preparation(s) Constituent with
known therapeutic activities are known, the
active ingredients should be standardized to
contain a defined amount of this/these
constituent(s)
 e.g : Ascorbic acid
o Secondary reference substance (working
standard)

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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

o The records should include information of:

 sample, instruments, equipment,
reagent/media/column, reference standard, refer
to testing method
 identity of the personnel involved in the
sampling, preparation and testing of the
samples.
 appendices containing the relevant recordings,
e.g. chromatograms and spectra.
o to ascertain traceability
Quality control data documentation shall implement good
documentation practices (ALCOA Principles):
o Attributable – data are identified with a specific
DOCUMENT
subject and a specific observer and recorder.
 Type of Document
(Password, audit trail, esignature and name &
o Specifications (refer to Chapter 5)
authentic signature)
o Testing Procedures o Legible – data are readable and understandable by
o Approved testing procedures shall refer to testing humans (reports, tables, and listings)
method described in specifications, and Internationally o Contemporaneous - data are recorded at the time
accepted method they are generated or observed. (Time stamps and
o SOPs related to QC activities time-limited entry)
o Records including Analysis worksheets and/or o Original – data are recorded for the first time. (Source
laboratory notebooks data and meta data)
o Analysis reports and/or certificates o Accurate – data are correct (data can be verified)
 DATA INTEGRITY is the assurance that data records are
accurate, complete, intake and maintained within there
original context including traceability to other data/records
o Data integrity: ALCOA ++ principles
 Complete: all data including repeat or reanalysis
perform from the sample
 Consistent: consistent application of data time
stamps in the expected sequence
 Enduring: recorded on controlled worksheets ,
laboratory logbook or electronic media
 Available: available, accessible for review/audit
for the lifetime of the record
o Data integrity applies to data recorded in:
 SOPs related to QC activities  electronic and
 paper format or
 a hybrid of both (paper and electronic)
 stored and retained in a manner that prevents modification,
damage or deterioration and/or loss
 held secure and in confidence
 retained for an appropriate period of time, generally shelflife
plus one year for finished product is recommended, unless
national regulations are more stringent or contractual
arrangements
 electronic data shall be backed-up regularly and stored in
secured place
 Data processing equipment
o Data may be recorded by :
 Quality control records  electronic data processing systems,
o records are made, manually and/or by recording  photographic,
instruments, during testing/analysis which  manual or other reliable means,
demonstrate required steps by the defined procedures  Detailed procedure relating to the system in use shall be
o laboratory should establish and maintain procedures available and the accuracy of the records shall be checked
for and verified.
 identification, collection, indexing, retrieval,  If documentation is handled by electronic data processing
storage, maintenance and disposal of and methods
access to all quality and technical/scientific  only personnel who have been authorized shall be able to
records enter or modify data in the computer and there shall be a
o data recorded in the analytical worksheet by the record of changes and deletions i.e. must have audit trail;
technician or analyst on consecutively numbered
pages.

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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

 access shall be restricted by passwords or other means and

the result of entry of critical data shall be independently
checked and verified

Sampling
Samples received by QC laboratory:
 routine for control: natural, starting, packaging materials and
finished products
 ongoing stability samples
 environmental monitoring: cleanliness of production area,
water as starting material and final rinsing for equipment
cleaning
 investigative testing: complaint, recall, deviation,
reprocessing
 must be taken from each batch and Sampling PLAN for Starting Material
 well documented in:  Examples of use of sampling plans n, p and r (Consider a
o Sampling form consignment of 40 containers (N) of a starting material)
o Sample Log book o n plan: samples taken from 7 containers selected at
 Due to herbal materials are an aggregate of individual random. The appearance and identity of each of these
plants and/or different parts of the same plant and thus have 7 samples is checked. If the results are concordant,
an element of heterogeneity, sampling should be carried out the 7 samples are combined to produce a single,
o by personnel with the necessary expertise composite sample from which an analytical sample is
Sampling procedure shall describe: prepared for full testing
 method of sampling o p plan, samples taken from each container. The
 sampling tools, to include instruction for cleaning and appearance and identity of each of these samples is
storage of sampling equipment checked. If the results are concordant, the samples
 sampling facility are appropriately combined to form 3 final, composite
 amount of the sample to be taken must be in accordance samples to be used for retention (or full testing if
with sampling plan required).
 instructions for any required subdivision of the sample o r plan, samples taken from each container. The
 type and condition of the sample container to be used appearance and identity of each of these samples is
 identification of containers sampled (label checked. If the results are concordant, 10 samples are
 the storage condition selected at random and individually subjected to full
 sampling forms to be used testing
Sampling Plan Sampling PLAN for Packaging materials
 Definition of Sampling Plan:  Examples of sampling plan include:
o description of the location, number of units and/or o Number of sample (n) = 1 + √N
quantity of material that should be collected, and o BS 6001-1, ISO 2859 or ANSI/ASQCZ1.4-1993. The
associated acceptance criteria. objective is to ensure that there is a low probability of
o An example of sampling plan for starting materials accepting material that does not comply with the
 N plan, p plan, r plan predefined Acceptance Quality Level (AQL)
Sampling PLAN for Natural materials (medicinal plants)
 Initial inspection to each container shall indicate that the lot
is uniform
 Sample taken

 Samples should be taken from the top, middle and

bottom of the container
 Dented containers must be subjected for sampling.
 Intermediate, bulk and finished products
o Samples should be taken from the start, middle and
end of the process

Sampling Facility
 Sampling should be conducted at defined locations and by
procedures designed to prevent contamination of the material
sampled and contamination of other materials
 Where possible, sampling should be performed in an area or
booth designed for this purpose, although this will not be

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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

possible where samples are required to be taken from a

production line (e.g. in-process control samples).
 Cleanliness class of sampling facility should be the same as
where the material is processed
Testing
 The area in which the sample was taken should be recorded
in the sampling form
 Reference samples shall be representative of the batch of
materials or products from which they are taken
 Sample containers shall bear a label indicating
o name of materials,
o batch number (internal system),
o date of sampling and
o containers from which samples have been drawn
 Containers from which samples have been drawn shall bear
label “SAMPLE TAKEN”
 Usage and cleaning status of sampling devices should be
documented in log book
 Example of Sampling tools  All testing operations described in the marketing authorization
shall be carried out according to
o approved methods which shall be internationally
accepted (Refer to Appendix 1: List of Internationally
Accepted References for Test Methods) or
o other validated test methods
 The test results shall be recorded in ANALYTICAL
WORKSHEET and the records shall include at least:
o Name of the material or product and, where
applicable, dosage form
o Batch number, expiry date and, where appropriate, the
manufacturers and/or supplier
o References to the relevant specifications and testing
Sample Registration
procedures
 Samples should be registrated / written in log book o Test results, including observations and calculations,
containing:
and reference to any certificates of analysis
o registration number
o System Suitability Test (SST) shall be carried out
o date of receipt
where applicable
o sample identification as described in sample’s o Dates of testing, the name of the analyst and the
label name of the external laboratory, if applicable
o specific chemistry/microbiology lab to which the o Date and signature of the persons who performed the
sample is forwarded. testing and who verified the testing and the
Sample Storage calculations, where appropriate
 The sample prior to testing, the retained sample and any o A clear statement of release or rejection (or other
portions of the sample remaining after performance of all status decision) and the dated signature of the
the required tests should be stored securely, taking into designated responsible person
account the storage conditions specified for the sample Release/ Reject
Reference Sample
 Release and rejection procedure shall be available for
 Finished Products materials and products,
o Each batch shall be retained till one year after
 Release for sale of finished product shall be done by the QA /
the expiry date. Finished products shall usually QC authorised person Finished product assessment shall
be kept in their final packaging and stored include production condition, results of in-process testing,
under the recommended conditions. review of manufacturing (including packaging) documentation,
 Starting materials (other than natural materials, solvents, in compliance with Finished Product Specification and
gases and water) shall be retained for at least two years examination of final finished pack.
after release of the product if their stability allows. This Contract analysis
period may be shortened if their stability, as mentioned in  Contract analysis can be performed
the relevant specification, is shorter. o In case no availability of facilities for testing
 Reference samples of materials and products shall be of o Requirement of Contract Analysis should be comply
a size sufficient to permit at least a full re-examination
 Out of specification (OOS) or significant atypical trends shall
be investigated.
 FLOW OF OOS:

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 Pharmaceutical Lesson 2.4: PQS: GOOD QUALITY CONTROL LABORATORY
Manufacturing PRACTICE
AY 2023-2024 Dr.Kim Alexandra Pedrosa
1st Semester 08/24/2203

maintained. This summary shall be subjected to periodic

review.
 Where on-going stability studies are carried out at a site other
than the site of manufacture of the bulk or finished product,
there should be a written agreement between the parties
concerned.
 Results of on-going stability studies should be available at the
site of manufacture for review by the competent authority
 Out of specification or significant atypical trends shall be
investigated.
 Any confirmed out of specification result, or significant
negative trend, shall be reported to the relevant competent
authorities.
 Monitoring of Environment and Water Quality
 The possible impact on batches on the market shall be
o Data from environmental monitoring, where appropriate
considered in accordance with Chapter 9
shall be available
 Complaints and Product Recalls of the GMP Guide and in
o Program for monitoring should be available for
consultation with the relevant competent authorities
 Water for production
 Production environment

On-going Stability Programme

 Purpose of the on-going stability program is REFERENCES
o To monitor the product over its shelf life (in the market)  ASEAN Guidelines on Good Manufacturing Practice for
and to determine that the product remains, within Traditional Medicines and Health Supplements.
specifications under the labelled storage conditions  ASEAN Guidelines on Stability Study and Shelf-Life of
 Selection of batches Traditional Medicines and Health Supplements.
o Unless otherwise justified, at least one batch per year  WHO TRS 937, 2006, Annex 3, Supplementary
of product manufactured in every primary packaging Guidelines on GMP for the Manufacture of Herbal
type Medicines.
 Follow-up stability for risk product should be conducted:  WHO TRS 957, 2010, Annex 1, WHO Good Practices
o After any significant change or forPharmaceutical Quality Control Laboratories
o Significant deviation to the process or package.  Quality Control Methods for Medicinal Plant Material,
o Any reworking, reprocessing or recovery operation WHO Geneva 1998
 Stability study requirements  WHO TRS 961, 2011, Annex 2, WHO Good Practices for
o Refer to ASEAN Guidelines on Stability Study and Shelf Pharmaceutical Microbiology Laboratories.
Life TM and HS (Annex 5 of the ASEAN Agreements on  MHRA GMP Data Integrity Definitions and Guidance for
TM and HS) Industry, March 2015
o Storage condition and testing frequency  WHO TRS 929, 2005, Annex 4, WHO Guidelines for
Sampling of Pharmaceuticals Product and Related
Materials.

 Written PROTOCOL should be available and define:

o Number of batch(es) per strength and different batch
sizes, where applicable
o Relevant physical, chemical, microbiological and
biological test methods, stability indicating parameters,
where applicable
o Acceptance criteria
o Reference to test methods
o Description of the container closure system(s)
o Testing intervals (time points)
o Description of the conditions of storage
o Other applicable parameters specific to the finished
product
 Stability chamber/room used to store the samples, should be
verified/qualified, maintained and monitored
 A summary of all the data generated, including any interim
conclusions on the programmed, shall be written and
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