Apt.

Program
Faculty of Pharmay
Universitas Hasanuddin

PHARMACEUTICAL
INDUSTRY
Achmad Himawan, S.Si., M.Si., PhD. Apt.
Pharmaceutics Lab.
Dept. of Pharmaceutical Science & Technology
[email protected]
Week 9 PHARMACEUTICAL QUALITY CONTROL
1. General overview
2. Raw and packaging materials
3. In process control
4. Finished goods
5. Stability testing and programme
6.Environmental monitoring
7. OOX handling
GENERAL OVERVIEW Section 1
Quality control in Indonesian GMP
Quality control in Indonesian GMP
• Umum
• Cara berlaboratorium pengawasan mutu yang baik
• Dokumentasi
• Pengambilan sampel
• Pengujian
• Persyaratan pengujian
• Program stabilitas on-going
RAW AND PACKAGING MATERIALS Section 2
Sample management
• Written procedures for sampling methods for all materials
• Sampling plans and procedures should be based on scientifically
sound methods
• Samples should be representative of the batch of materials
• Sampling methods should specify the number of containers to be
sampled, which part of the container to sample, and the number of
materials in each container
• Containers should be appropriately marked, stored, and disposed
Sampling booth
Raw materials
Sampling plan for raw materials
n plan
✓ Only when the material to be sampled is considered uniform and is supplied from a recognized source
Sample can be withdrawn from any part of the container (usually from the top layer)
✓ n = 1 + √N
✓ N number of sampling units in the consignment
✓ If N ≤ 4 than every container is sampled

p plan
✓ May be used when the material is uniform, is received from a recognized source and the main purpose is to
test for identity
✓ p = 0.4 √ N

r plan
✓ May be used when the material is suspected to be non uniform and/or is received from a source that is not
well unknown
✓ May also be used for herbal medicinal product used as starting material
✓ R = 1.5 √N
Packaging materials
Sampling plan for packaging materials

https://www.qima.com/aql-acceptable-quality-limit
IN PROCESS CONTROL Section 3
In-Process Control
 In-Process Control

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211/subpart-F/section-211.110
In-Process
Control
FINISHED GOODS Section 4
Finished goods testing
Finished goods testing
• Test to release
• According to USP and established in-house parameter
• Various analytical techniques, depends on the parameter
being tested
STABILITY TESTING AND PROGRAMME Section 5
Stability testing

Pre-
On-going
market
Pre-market
 ICH Q1A
Pre-market

ICH Q1F
Photostability (ICH Q1B)

 What to test

Light source →
Bracketing (Q1D)
Bracketing is the design of a stability
schedule such that only samples on
the extremes of certain design factors
(e.g., strength, container size and/or
fill) are tested at all time points as in a
full design. The design assumes that the
stability of any intermediate levels is
represented by the stability of the
extremes tested.
The use of a bracketing design would
not be considered appropriate if it
cannot be demonstrated that the
strengths or container sizes and/or fills
selected for testing are indeed the
extremes.
Matrixing (Q1D)
Matrixing is the design of a stability schedule
such that a selected subset of the total
number of possible samples for all factor
combinations would be tested at a specified
time point. At a subsequent time point,
another subset of samples for all factor
combinations would be tested. The design
assumes that the stability of each subset of
samples tested represents the stability of all
samples at a given time point. The differences
in the samples for the same drug product
should be identified as, for example, covering
different batches, different strengths,
different sizes of the same container closure
system, and possibly, in some cases, different
container closure systems.
Extrapolation (ICH 1E)
Extrapolation (ICH 1E)
On-going stability testing
On-going
stability
testing
Retained samples
ENVIRONMENTAL MONITORING Section 5
Environmental monitoring
Environmental monitoring Passive air monitoring
(Settle plate)

Active air monitoring

(Air sampler)
Contact plate
Water monitoring

PW WFI PG Condensate*
Conductivity ≤ 1.3 μS/cm ≤ 1.3 μS/cm ≤ 1.3 μS/cm
Heavy metal ≤ 0.1 ppm (as Pb) ≤ 0.1 ppm (as Pb) ≤ 0.1 ppm (as Pb)
Nitrate ≤ 0.2 ppm ≤ 0.2 ppm ≤ 0.2 ppm
TOC <500 ppm <500 ppm <500 ppm
TMC ≤ 100 cfu/mL ≤ 10 cfu/100 mL NA
Endotoxin NA ≤ 0.25 EU/mL ≤ 0.25 EU/mL

*measured as WFI except for its microbial load

Air (and production room) monitoring
“at rest” and “in operation”
Active Passive Contact plate
Class
(cfu/m3) (cfu/4 hours) (cfu/plate)
A <1 <1 <1

B 10 5 5

C 100 50 25

D 200 100 50
Air (and production room) monitoring
“at rest” and “in operation”
OOX HANDLING Section 6
General definitions
• Written procedures for sampling methods for all materials
• Sampling plans and procedures should be based on scientifically sound
methods
• Samples should be representative of the batch of materials
• Sampling methods should specify the number of containers to be sampled,
which part of the container to sample, and the amount of materials in each
container
• Sampling should be conducted at defined locations and to prevent
contamination
• Containers from which samples are withdrawn should be opened carefully
and subsequently re-closed
• Containers should be marked clearly
“X” in “OOX”

OOX Stand for Out of …. (Something)

▪ Out of Specification (OOS)
▪ Out of Expectation (OOE) / Atypical Result
▪ Out of Trend (OOT)
General definitions
Out of Specification

Does not comply with the pre determined acceptance criteria (i.e. for
example, filed applications, drug master files, approved marketing
submissions, or official compendia or internal acceptance criteria).

Out of Expectation

Results that are still within specification but are unexpected,

questionable, irregular, deviant or abnormal.

Out of Trend

An out come of testing on stability result that does not follow the
expected trend
OOS in Indonesian GMP
 OOX visualisation

Source: ISPE Seminar on OOX Handling

MHRA OOX overview
Phase 1a investigation
Phase la investigation is to determine whether there has
been a clear obvious errors due to external circumstances
such as power failure or those that the analyst has detected
prior to generating data such as spilling sample that will
negate the requirement of a Phase Ib investigation.

For microbiological analysis this may be after the analysis has

been completed and reviewed during reading of the samples.

It is expected that these issues are trended even if a

laboratory investigation lb or ll was not raised.
Phase 1b investigation
Phase Ib Investigation – Initial Investigation
conducted by the analyst and supervisor using
the Laboratory Investigation Checklist

For microbiological analysis where possible once

a suspect result has been identified ensure all
items related to the test failure are retained
such as other environmental plates, dilutions,
ampoules/vials of product, temperature data,
auto-pipettes, reagents – growth media.

The Analyst and Supervisor investigation should

be restricted to data / equipment / analysis
review only

On completion of the Analyst and Supervisor

investigation re-measurement can start once the
hypothesis plan is documented and is only to
support the investigation testing.
Phase II investigation Phase II conducted when the phase I investigations
did not reveal an assignable laboratory error. Phase
II investigations are driven by written and approved
instructions against hypothesis. Prior to further
testing a manufacturing investigation should be
started to determine whether there was a possible
manufacturing root cause.

It is important when considering performing

additional testing that it is performed using a
predefined retesting plan to include retests
performed by an analyst other than the one who
performed the original test. A second analyst
performing a retest should be at least as experienced
and qualified in the method as the original analyst.

If the investigation determines analyst error all

analysis using the same technique performed by the
concerned analyst should be reviewed.
Phase II investigation (cont.)
Phase III investigation
The phase III investigation should review the completed manufacturing investigation and combined laboratory
investigation into the suspect analytical results, and/or method validation for possible causes into the results
obtained.

To conclude the investigation all of the results must be evaluated.

The investigation report should contain a summary of the investigations performed; and a detailed conclusion.

For microbiological investigations ,where appropriate, use risk analysis tools to support the decisions taken and
conclusions drawn. It may not have been possible to determine the actual root cause therefore a robust most
probable root cause may have to be given.

Once a batch has been rejected there is no limit to further testing to determine the cause of failure, so that
corrective action can be taken.

The decision to reject cannot be reversed as a result of further testing.

Always remember …
▪ Do not test till pass
▪ Do not jump to conclusion too soon
▪ Follow gdp and data integrity
▪ Understand the phase of investigation
▪ Follow oos flow step by step properly
▪ Proper documentation especially on hypothesis test
▪ Track back the analysis test in detail documentation physical movement
instrument electronic data record
▪ Record all data and justify it
▪ Prepare scientific sound report with patient safety as utmost important
aspect before batch disposition
In conclusion
▪ QC covers analytical activities that are used to measure the quality of
the raw materials, packaging materials, intermediate/bulk products,
finished products and the environment where the products are
produced
▪ QC covers the stability testing of the products
▪ QC covers the handling of OOX
 THANK YOU
Achmad Himawan [email protected]
+62 878-4152-2172
@chmadhimawan
@chmadhimawan
http://farmasi.unhas.ac.id/4030-2/