Workshop on Quality Assurance and GMP of Multisource HIV/AIDS medicines

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Workshop 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

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GMP - 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

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Characteristics of analytical procedures (1)

• Accuracy (also termed trueness)
• Precision
• Repeatability
• intermediate precision (within-laboratory
  variation)
• reproducibility (inter-laboratory variation)
• Robustness, ruggedness

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Characteristics of analytical procedures (2)

• Linearity
• Range
• Specificity (selectivity)
• Sensitivity (versus robustness)
• Limit of detection
• Limit of quantitation

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Accuracy and precision
Inaccurate and imprecise
Accurate
Accurate and precise
Precise
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Classes 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

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Criteria 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
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General requirements

• Qualified and calibrated instruments
• Documented methods
• Reliable reference standards
• Qualified analysts
• Sample integrity
• Change control (e.g., synthesis, FPP composition)

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HPLC Method Development and Validation for
Pharmaceutical Analysis by Ghulam A. Shabir

• Pharmaceutical Technology Europe, 1 March 2004

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Prequalification 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.

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HPLC system
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Linearity and range
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ICH 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.

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Accuracy
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).
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Specificity
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Specificity

• 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.

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Repeatability

• 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.

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Intermediate precision
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Limit 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.

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Limit 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.

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LOD, LOQ and SNT

• Limit of Quantitation (LOQ)
• Limit of Detection (LOD)
• Signal to Noise Ratio (SNR)

Peak BLOQ
Peak ALOD
noise
Baseline
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Analytical 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.
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Conclusion 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.

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Workshop 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

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Subjects 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

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WHO 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.

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WHO 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.

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Why 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.

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Pharmaceutical 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).

• GENERAL
• CONSIDERATIONS

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Potential 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)

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Manual 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)

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Automated 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)

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Documentation 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

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Cleaning 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)

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Frequency of Cleaning

• Cleaning between batches of the same product
  (abbreviated procedures)
• Cleaning between batches of different products
• Cleaning after maintenance
• Cleaning after accidental contamination

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Cleaning 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

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Validation 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.

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Validation 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.

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Validation 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.

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Approach for setting limits

1. Product specific cleaning validation for all
   products
2. Grouping into product families and choosing a
   worst case product
3. Grouping into risk categories (e.g., very soluble
   products, similar potency, highly toxic products
   or difficult to detect)
4. Setting limits on not allowing more than a
   certain fraction of carryover
5. Different safety factors for different dosage
   forms.

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Carry-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.)

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Carry-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).

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Analytical 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).

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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.

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An Illustrative Approach to Cleaning Validation

• ANTIRETROVIRAL
• FPP(s)

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Cleaning 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.

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Risk Analysis
RISK FACTORS
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Illustrative Indicators for Toxicity
Composite toxicity indicators may take into
account high activity, hypersensitizing
indicators, etc.
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Illustrative Categories for Solubility
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Illustrative Risk Analysis of ARV APIs
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Pharmaceutical Technology Europe, 1 February
2004Griet Van Vaerenbergh

• Cleaning Validation Practices Using a One-Pot
  Processor

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Summary

• 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.

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One-pot processor
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Acceptance 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.

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Acceptable 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.

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Theophylline sample analysis
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Mebendazole sample analysis
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Study 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.

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Main 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.

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THANK YOU
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