2005.03.03. dr. pogány - who, shanghai 1/60 workshop on quality assurance and gmp of multisource...

2005.03.03. Dr. Pogány - WHO, Shanghai 1/60

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

János Pogány, pharmacist, PhD, consultant to WHO

Shanghai, 01 March 2005E-mail: [email protected]

QUALIFICATION and VALIDATION II.


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


Characteristics of analytical procedures (1)

Accuracy (also termed trueness)

Precision Repeatability

intermediate precision (within-laboratory variation)

reproducibility (inter-laboratory variation)

Robustness, ruggedness


Characteristics of analytical procedures (2)

Linearity

Range

Specificity (selectivity)

Sensitivity (versus robustness)

Limit of detection

Limit of quantitation


Accuracy and precision

Inaccurate &imprecise

Inaccurate butprecise

Accurate butimprecise Accurate and precisePrecise Accurate

Inaccurate and imprecise


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


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


General requirements

Qualified and calibrated instruments

Documented methods

Reliable reference standards

Qualified analysts

Sample integrity

Change control (e.g., synthesis, FPP composition)

HPLC Method Development and Validation for Pharmaceutical

Analysis by Ghulam A. Shabir

Pharmaceutical Technology Europe, 1 March 2004


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.


HPLC system


Linearity and range


ICH requirements Concentration range 0.025–0.15 mg/mL (25–150% of the

theoretical concentration in the test preparation, n=3) 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.


Accuracy

The data show that the recovery of analyte in spiked samples met the evaluation criterion for accuracy (100 ± 2.0% across 80–120% of target concentrations).


Specificity


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.


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%.


Intermediate precision


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 signal:noise ratio

(SNR), usually between 3 and 2:1.

In this study, the LOD was determined to be

10ng/mL with a signal:noise ratio of 2.9:1.


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 10:1.

The LOQ was 20 ng/mL with a signal:noise ratio of 10.2. The RSD for six injections of the LOQ solution was ≤2%.


Limit of Quantitation (LOQ)

Limit of Detection (LOD)

Signal to Noise Ratio (SNR)

noise

Peak ALOD

Peak BLOQ

Baseline

LOD, LOQ and SNT


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.


Conclusion of validation study The relation between concentration and peak area

is linear in the range from 25 to 150%. R=1. 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.


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

János Pogány, pharmacist, Ph.D. Shanghai, 03 March 2005

E-mail: [email protected]

CLEANINGVALIDATION


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


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.


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.


Why do we validate cleaning processes? The cleaning processThe cleaning process is an integral part of the is an integral part of the

pharmaceutical manufacturing process.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.

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


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)


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)


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)


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


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)


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

Cleaning Validation Guidelines,Health Products and Food Branch Inspectorate,

Canada http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/clean_val_gui_entire_e.html

PRESENTATION IS LIMITED TO SOLID PHARMACEUTICAL

DOSAGE FORMS


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.


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.


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.


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.


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.)


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).


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).


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.

An Illustrative Approach to Cleaning Validation

ANTIRETROVIRAL

FPP(s)


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.


Risk Analysis

WATER SOLUBILITY

LOW MODERATE HIGH

TOXICITY

HIGH High High Moderate

MODERATE High Moderate Moderate

LOW Moderate Moderate Low

RISK FACTORS


Illustrative Indicators for Toxicity

LD50 (rat or /mouse/) Category

< 200 mg/kg High

200 – 2000 mg/kg Moderate

> 2000 mg/kg Low

Composite toxicity indicators may take into account high activity, hypersensitizing indicators,

etc.


Illustrative Categories for Solubility

LD50 (rat or /mouse/) Category < 200 mg/kg High 200 – 2000 mg/kg Moderate > 2000 mg/kg Low

Descriptive Term for Solubility (Ph.Eur.) Category

Very soluble (< 1 ml/g)Freely soluble (1 – 10 ml/g)Soluble (10 – 30 ml/g)

High solubility (<30 ml/g)

Moderately soluble Sparingly soluble (30 – 100 ml/g)Slightly soluble (100 – 1000 ml/g)

Moderate solubility(30 – 1000 ml/g)

Very slightly soluble (1000 – 10000 ml/g)Practically insoluble (> 1000 ml/g)Relatively insolubleInsoluble

Low solubility(> 1000 ml/g)


Illustrative Risk Analysis of ARV APIs

API TOXICITY INDICATOR

SOLUBILITY IN WATER

Abacavir Moderate High 77 mg/mL at 25oC

Efavirenz Low Low

Indinavir sulfate Low High 100 mg/ml

Lamivudine Low High

Nevirapine Low Low 90 μg/ml at 25°C

Ritonavir Low Low

Saquinavir Low Low

Stavudine Low High

Zidovudine Low High 20 mg/mL at 25oC

Pharmaceutical Technology Europe, 1 February 2004

Griet Van Vaerenbergh

Cleaning Validation Practices: Using a One-Pot Processor


SummaryThis 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.


One-pot processor


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 1:1000 dilution of the detergent solution.


Acceptable quantity of an API per swab Initial trials on the swab determined that the theophylline recovery was between 95–100%. Nevertheless, the Factor 2 for swab yield was maintained in the formula for calculating the acceptance criteria, to account for any operator influence.


Theophylline sample analysis


Mebendazole sample analysis


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.


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.


THANK YOU

谢谢 !

2005.03.03. dr. pogány - who, shanghai 1/60 workshop on quality assurance and gmp of multisource...

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