Title: Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines
1Workshop on Quality Assurance and GMP of
Multisource HIV/AIDS medicines
QUALIFICATION and VALIDATION II.
- János Pogány, pharmacist, PhD,
- consultant to WHO
- Shanghai, 01 March 2005
- E-mail pogany_at_axelero.hu
2GMP - 4.11 Analytical methods, computers and
cleaning procedures
- It is of critical importance that particular
attention is paid to the validation of analytical
test methods, automated systems and cleaning
procedures. - Validation of analytical procedures used in the
examination of pharmaceutical materials (WHO
Expert Committee on Specifications for
Pharmaceutical Preparations. 32nd Report. Geneva,
WHO, 1992 (WHO Technical Report Series, No. 823). - Text on Validation of Analytical Procedures Q2A
(1994) - Validation of Analytical Procedures Methodology
Q2B (1996) - ICH Harmonized Tripartite Guidelines
3Characteristics of analytical procedures (1)
- Accuracy (also termed trueness)
- Precision
- Repeatability
- intermediate precision (within-laboratory
variation) - reproducibility (inter-laboratory variation)
- Robustness, ruggedness
4Characteristics of analytical procedures (2)
- Linearity
- Range
- Specificity (selectivity)
- Sensitivity (versus robustness)
- Limit of detection
- Limit of quantitation
5Accuracy and precision
Inaccurate and imprecise
Accurate
Accurate and precise
Precise
6Classes of analytical tests
- The objective of validation of an analytical
procedure is to demonstrate that it is suitable
for its intented purpose. - Class A To establish identity
- Class B To detect (Bd) and quantitate (Bq)
impurities - Class C To determine quantitatively the
concentration, or assay - Class D To assess characteristics
- Other classes not covered in the guides
7Criteria for analytical classes
Criteria A Bq Bd C D
Accuracy X X X
Precision X X X
Robustness X X X X X
Linearity and range X X X
Specificity X X X X X
Limit of detection X
Limit of quantitation X
8General requirements
- Qualified and calibrated instruments
- Documented methods
- Reliable reference standards
- Qualified analysts
- Sample integrity
- Change control (e.g., synthesis, FPP composition)
9HPLC Method Development and Validation for
Pharmaceutical Analysis by Ghulam A. Shabir
- Pharmaceutical Technology Europe, 1 March 2004
10Prequalification requirements
- Analytical method validation is required by WHO
for the prequalification of product dossiers.
Non-compendial ARV APIs and FPPs were/are tested
with methods developed by the manufacturer. - Analytical methods should be used within GMP and
GLP environments, and must be developed using the
protocols and acceptance criteria set out in the
ICH guidelines Q2A and Q2B.
11HPLC system
12Linearity and range
13ICH requirements
- Concentration range 0.0250.15 mg/mL (25150 of
the theoretical concentration in the test
preparation, n3) - Regression equation was found by plotting the
peak area (y) versus the analyte concentration
(x) expressed in mg/mL y 3007.2x 4250.1 (r2
1.000). - The regression coefficient demonstrates the
excellent relationship between peak area and
concentration of analyte. - The analyte response is linear across 80-120 of
the target progesterone concentration.
14Accuracy
The data show that the recovery of analyte in
spiked samples met the evaluation criterion for
accuracy (100 2.0 across 80120 of target
concentrations).
15Specificity
16Specificity
- An example of specificity criterion for an assay
method is that the analyte peak will have
baseline chromatographic resolution of at least
2.0 from all other sample components. - In this study, a weight of sample placebo
equivalent to the amount present in a sample
solution preparation was injected to demonstrate
the absence of interference with progesterone
elution. Former slide demonstrates specificity.
17Repeatability
- The repeatability precision obtained by one
analyst in one laboratory was 1.25 RSD for the
analyte and, therefore, meets the evaluation
criterion of RSD 2.
18Intermediate precision
19Limit of detection
- The limit of detection (LOD) is defined as the
lowest concentration of an analyte in a sample
that can be detected, not quantified. It is
expressed as a concentration at a specified
signalnoise ratio (SNR), usually between 3 and
21. - In this study, the LOD was determined to be
10ng/mL with a signalnoise ratio of 2.91.
20Limit of quantitation
- The limit of quantitation (LOQ) is defined as the
lowest concentration of an analyte in a sample
that can be determined with acceptable precision
and accuracy under the stated operational
conditions of the method. The ICH has recommended
a signal noise ratio (SNR) of 101. - The LOQ was 20 ng/mL with a signalnoise ratio of
10.2. The RSD for six injections of the LOQ
solution was 2.
21LOD, LOQ and SNT
- Limit of Quantitation (LOQ)
- Limit of Detection (LOD)
- Signal to Noise Ratio (SNR)
Peak BLOQ
Peak ALOD
noise
Baseline
22Analytical solution stability
Standard and sample solutions stored in a capped
volumetric flask on a lab bench under normal
lighting conditions for 24 h were shown to be
stable with no significant change in progesterone
concentration during this period.
23Conclusion of validation study
- The relation between concentration and peak area
is linear in the range from 25 to 150. R1. - Accuracy shows a mean with a RSD of 0.59 over the
the range from 50 to 150. - The method is specific in the given formulation.
- Repeatability and intermediate precision are well
within the 2 RSD criterion. - LOD is 10 ng/mL and LOQ is 20 ng/mL.
- The analytical solution is stable for 24 hours.
24Workshop on Quality Assurance and GMP of
Multisource HIV/AIDS medicines
CLEANING VALIDATION
- János Pogány, pharmacist, Ph.D.
- Shanghai, 03 March 2005
- E-mail pogany_at_axelero.hu
25Subjects for Discussion
- Regulatory background
- General considerations
- Cleaning validation guideline Canada
- An illustrative approach to the cleaning
validation of antiretroviral (ARV) active
pharmaceutical ingredient(s) API(s - A case study from literature
- Conclusions
26WHO GMP
- 4.11 It is of critical importance that particular
attention is paid to the validation of ...
cleaning procedures. - 16.11 Contamination of ... a product by another
material or product must be avoided. This risk of
accidental cross contamination arises from ...
products in process, from residues on equipment.
Among the most hazardous contaminants are highly
sensitizing materials ... and highly active
materials.
27WHO GMP
- 16.15 Before any processing operation is started,
steps should be taken to ensure that the work
area and equipment are clean. - 16.18 Time limits for storage of equipment after
cleaning and before use should be stated and
based on data.
28Why do we validate cleaning processes?
- The cleaning process is an integral part of the
pharmaceutical manufacturing process. - Industry should view cleaning of equipment as the
first manufacturing step. (It will have effect on
the safety, efficacy and quality of the batch to
be manufactured.) - A cleaning process must be chosen based on
products (e.g., ARVs, solid dosage forms),
objectives, resources, and limitations within
each manufacturing company.
29Pharmaceutical Process Validation Second
Edition, Revised and Expanded, edited by Ira R.
Berry and Robert A. Nash, Marcel Dekker, Inc.,
New York Basel Hong Kong (1993).
30Potential Contaminants
- Chemical contamination
- Product residues
- Decomposition residues
- Cleaning or disinfecting agent residues
- Microbiological contamination
- Bacteria, moulds, pyrogens
- Unintended materials
- Airborne (particulate) matter
- Lubricants, ancillary material (e.g. pieces of
brushes)
31Manual Cleaning Procedures
- Equipment disassembly (if required)
- Prewash and inspection (most visible material
removed) - Wash (cleaning agent, temperature, multiple steps
until visually clean) - Initial rinses (rinse water, temperature)
- Final rinse (minimum dissolved solids,
microorganisms) - Reassembly (if required)
32Automated Cleaning Procedures
- Clean-in-place (CIP) systems (dishwasher-type
equipment) - portable (tank and pump assemblies on wheels)
- stationery, cabinet-type
- Control system qualification (reproducibility,
water temperature control) - Sampling (sampling port, pause capability)
- Material supply (hard-plumbed supply lines,
volume and dispensing controls, potential impact
of long storage periods)
33Documentation and Traceability
- Equipment identification
- Equipment use, maintenance and cleaning records
- Labeling
- Cleaning equipment maintenance and calibration
- Utilities (water for injection (WFI), purified
water, steam and compressed air systems)
qualified and validated. - Standard Operating Procedure(s) SOP(s)
- Personnel training
34Cleaning Materials and Tools
- Solvents (source and quality controlled)
- Cleaning agents (acids, bases, surfactants, etc.,
qualified type and brand QC controlled) - Ancillary utilities (steam and compressed air
qualified) - Scrubbing agents (compression of placebo tablets
to clean punches and dies) - Cleaning tools (standard sets of brushes, rags,
sponges) - Equipment (thermometers, CIP systems consisting
of tanks, metering pumps, heat exchangers, etc.
maintaned and kept in calibrated status)
35Frequency of Cleaning
- Cleaning between batches of the same product
(abbreviated procedures) - Cleaning between batches of different products
- Cleaning after maintenance
- Cleaning after accidental contamination
36Cleaning Validation Guidelines,Health Products
and Food Branch Inspectorate, Canada
http//www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/cl
ean_val_gui_entire_e.html
- PRESENTATION IS LIMITED TO SOLID PHARMACEUTICAL
DOSAGE FORMS
37Validation of cleaning processes
- Equipment cleaning validation may be performed
concurrently with actual production steps during
process development and clinical manufacturing.
Validation programs should be continued through
full-scale commercial production. - All pertinent parameters should be checked to
ensure the process, as it will ultimately be run
is validated. Therefore, if critical temperatures
are needed to effect cleaning, then these should
be verified. Any chemical agents added should be
verified for type as well as quantity. Volumes of
wash and rinse fluids, and velocity measurements
for cleaning fluids should be measured as
appropriate.
38Validation of cleaning processes
- Validation of cleaning processes should be based
on a worst-case scenario including - challenge of the cleaning process to show that
the challenge soil can be recovered in sufficient
quantity or demonstrate log removal to ensure
that the cleaning process is indeed removing the
soil to the required level, and - the use of stress cleaning parameters such as
overloading of contaminants, overdrying of
equipment surfaces, minimal concentration of
cleaning agents and/or minimum contact time of
detergents.
39Validation of cleaning processes
- At least three (3) consecutive applications of
the cleaning procedure should be performed and
shown to be successful in order to prove that the
method is validated.
40Approach for setting limits
- Product specific cleaning validation for all
products - Grouping into product families and choosing a
worst case product - Grouping into risk categories (e.g., very soluble
products, similar potency, highly toxic products
or difficult to detect) - Setting limits on not allowing more than a
certain fraction of carryover - Different safety factors for different dosage
forms.
41Carry-over of product residues
- NMT 0.1 of the normal therapeutic dose of any
product to appear in the maximum daily dose of
the following product (may not be acceptable for
parenterals). - NMT 10 ppm of any product to appear in another
product (may not be acceptable for parenterals). - No quantity of residue to be visible on the
equipment after cleaning procedures are
performed. (Spiking studies should determine the
concentration at which most active ingredients
are visible.)
42Carry-over of product residues
- Residues levels that do not interfere with
subsequent manufacturing processes. - For certain allergenic ingredients, penicillins,
cephalosporins or potent steroids and cytotoxics,
the limits should be below the limit of detection
by best available analytical methods. In practice
this may mean that dedicated plants are used for
these products. - Acceptable limits should be defined for detergent
residues after cleaning (there is no normal
therapeutic dose, thus e.g. the limit of
detection of the most toxic component).
43Analytical methods
- The analytical methods used to detect residuals
or contaminants should be specific and be
validated before the cleaning validation study is
carried out. - The specificity and sensitivity of the analytical
methods should be determined. - The analytical method and the percent recovery of
contaminants should be challenged in combination
with the sampling method(s).
44 Sampling and related issues
- Direct surface sampling (swab method)
- Indirect sampling (use of rinse solutions)
- Indirect testing such as monitoring conductivity
may be of some value - In terms of cross-contamination, the main concern
is residue left on the internal product-contact
surfaces of the manufacturing equipment.
45An Illustrative Approach to Cleaning Validation
46Cleaning validation (master) plan
- Validation plan is based on risk analysis.
- Cleaning of individual pieces of the
manufacturing and packaging equipment is
validated with products selected as the worst
case. - The three regulatory consecutive batches can be
extended to include potentially the last batches
of one or more campaign productions - Water solubility, toxicity and risk analysis data
of all ARV APIs.
47Risk Analysis
RISK FACTORS
48Illustrative Indicators for Toxicity
Composite toxicity indicators may take into
account high activity, hypersensitizing
indicators, etc.
49Illustrative Categories for Solubility
50Illustrative Risk Analysis of ARV APIs
51Pharmaceutical Technology Europe, 1 February
2004Griet Van Vaerenbergh
- Cleaning Validation Practices Using a One-Pot
Processor
52Summary
- This article describes the use of a one-pot
processor for the cleaning and cleaning
validation of two drug compounds water-soluble
theophylline and water-insoluble mebendazole.
Both substances were produced using wet
granulation and microwave drying, after which the
processor was cleaned using its clean-in-place
(CIP) system. Swab samples were taken from areas
considered critical during processing and
analysed for remains of active ingredient. It was
concluded from the results that the processor's
CIP system is capable of removing both APIs to a
level well within accepted regulations.
53One-pot processor
54Acceptance criteria
- 10-ppm criterion
- absolute mass criterion NMT 1 µg/cm2
- for residual detergent traces the conductivity
of the final rinsing water should be lower than
the conductivity of a 11000 dilution of the
detergent solution.
55Acceptable quantity of an API per swab
- Initial trials on the swab determined that the
theophylline recovery was between 95100.
Nevertheless, the Factor 2 for swab yield was
maintained in the formula for calculating the
acceptance criteria, to account for any operator
influence.
56Theophylline sample analysis
57Mebendazole sample analysis
58Study conclusions
- This study has shown that the CIP system of this
one-pot processor is capable of removing both
water-insoluble mebendazole and water-soluble
theophylline from the system to a level
significantly less than acceptable maxima.
Although certain areas show a larger variation in
results than others, the reproducibility of the
cleaning cycle can be considered good, as the
results for all areas were always consistent.
59Main Points Again
- Validation of equipment cleaning processes is
critical to safety, efficacy and quality of FPPs. - There is no generally accepted approach to
cleaning validation. - One possible approach is risk analysis and
selection of worst case for each item of
equipment. - CIP equipment must be qualified and the cleaning
processes must be validated.
60THANK YOU
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