Analytical Method & Technology Transfer Ispe Guide

ISPE Good Practices Guide: Analytical Methods/Technology Transfer

Prepared and presented by:Gilberto González-RiveraIPR Pharmaceuticals, Inc.

Technology Transfer Guide

Presents a clear and concise standardized process for transferring technology between two parties and recommends a minimum base of documentation in support of the transfer request.

The Guide is divided into three segments:Active Pharmaceutical Ingredients (API's)Dosage FormsAnalytical Methods

Published by the International Society of Pharmaceutical Engineers (ISPE) in collaboration with the US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS), with input from the European regulatory authorities and submission to the Japanese Ministry of Health and Welfare (MHW).

Technology Transfer Guide

Background

The cost and time required to transfer technology, in many cases, has risen due to inconsistent interpretation of regulatory requirements. The ISPE and technical representatives from a broad base of healthcare companies (e.g. pharmaceutical, device, biotechnology) recognized the need to develop guidance in the area of technology transfer.

Objective

To describe the appropriate information set that needs to be compiled, to support the manufacture of the product and provide regulatory filing documents.

To provide guidance on effective approaches for ensuring this information is available at "point of use". Where guidance on specific topics already exists this will be referenced.

Definitions

Acceptance Criteria aNDA API Automated/Robotic Bracketing Commissioning Critical Development Unit Direct Impact System Enhanced Design Review Expiration Date

F2 Impurity

IQ, OQ, PQ pH Q Quantitation Limit Receiving Unit Reporting Limit Retest Date Rf value Qualification Batches

Definitions

Technology Transfer:The systematic procedure that is followed in order to

pass the documented knowledge and experience gained during development and/or commercialization to an appropriate, responsible and authorized party.

Embodies both the transfer of documentation and the demonstrated ability of a Receiving Unit to effectively perform the critical elements of transferred technology, to the satisfaction of all parties and any, or all, applicable regulatory bodies.

Planning and Success Criteria

Technology transfer can be considered successful if a Receiving Unit can routinely reproduce the transferred product, process, or method against a predefined set of specifications as agreed with the Sending Unit and/or a Development Unit.

The success of a technology transfer project will be largely dependent upon the skill and performance of individuals assigned to the project from both the Sending Unit and the Receiving Unit. There should be a precise understanding of each team member's role and responsibility.

Analytical Methods Transfer

Note to the Reader

"The success of a technology transfer will be based largely on documented evidence that a method, process, or product can be reproduced against a pre-defined set of specifications. Given this premise and the fact that analytical testing is likely to be the foundation from which many determinations of success will be made, the authors of this document have included what are believed to be reasonable examples of analytical method transfer criteria. These are, however only examples and the user is free to apply whatever standard they feel appropriate for the task".

Scope

The procedure described in this guide concerns the transfer of analytical methodology between laboratories for the testing of pharmaceutical products, their ingredients, and cleaning (residue) samples.

It includes release, stability, and in-process testing for solids, semi-solids, parenterals, liquids, transdermal, inhalation products and ophtalmics, in addition to API's and critical excipients (where necessary)

Responsibilities

Sending Unit (SU):Create the transfer protocolExecute trainingAssist in analysisAcceptance Criteria

Receiving Unit (RU):Qualified instrumentationPersonnelSystems (Materials, Utilities, SOP's, etc)Executes the protocol

Methods to be Transferred

Solid Doses:AssayContent UniformityImpurities / DegradantsDissolution / Release RateIdentificationCleaning ValidationMicrobiological

Pre-transfer Activities

The RU should be provided with and review analytical methods prior to their transfer.

The SU and the RU should formally agree criteria for success before execution of the transfer protocol.

The SU should provide training to the RU. This should include a review of the methods and transfer protocol, as well as laboratory work, if possible. Training should be documented.

Transfer Protocol

Objective Scope Responsibilities Materials/Methods/Equipment Experimental Design Acceptance Criteria Documentation

Transfer Protocol

Deviations References Signature/Approval Page Reference samples, actives, intermediates,

and finished products

Transfer Protocol

The Guide recommends that acceptance criteria are established prior to the method transfer.

Acceptance criteria should be based on the intended use of the method, validation of the method, and historical data generated by the Sending Unit.

Transfer Report

Should include conclusions regarding the success of the transfer and confirm whether the receiving site is qualified to perform each analytical method.

Any deviation should be discussed and justified in the transfer report.

Experimental Design / Acceptance Criteria

Assay

• At least two (2) analysts at each laboratory should independently analyze three (3) lots in triplicate; resulting in eighteen (18) different executions of the method.

• For products with different strengths, bracketing may be appropriate.

• Each analyst should use a different set of the same instrumentation and/or columns and independently prepare all solutions.

• All applicable system suitability criteria should be met.

Acceptance Criteria

• May be statistically derived:– Two one-sided T-test intersite differences of

less than or equal to 2% with 95% confidence.

• May be based on a direct comparison of the means and the variability.

Content Uniformity

• Two (2) analysts of each laboratory analyze at least one sample lot.

• For products with multiple strengths bracketing may be appropriate.

• Each analyst should use a different set of the same instrumentation and/or columns and independently prepare all solutions.

• All applicable system suitability criteria should be met.

Acceptance Criteria

• May be statistically derived:– Two one-sided T-test intersite differences of

less than or equal to 3% with 95% confidence.

• Can be based on absolute difference of the means:– Values within ± 3%.

• Data variance (%RSD) at both laboratory should be compared.

Impurities / Degradant

• Two (2) analysts at each site analyze three (3) lots in duplicate (triplicate if done together with the assay) on different days using different sets of the same instrumentation and columns, if possible.

• All applicable system suitability criteria must be met.

• Limit of Quantitation (LOQ) should be confirmed at the RU in addition to response factors for substances whose amounts are calculated from their response relative to the drug peak.

Impurities / Degradant

• Samples to be tested at both laboratories are similar (representative of the batch) with regard to age, homogeneity, packaging, storage, etc.

• If typical samples do not contain impurities above the reporting limit, the use of spiked samples (if available) will be necessary to show equivalency between the laboratories.

Acceptance Criteria

• For fairly high levels of impurities, a statistical analysis may be used:– Two one-sided T-test intersite differences of

less than or equal to 10% with 95% confidence.

• For impurities that are at lower levels but above the reporting limit, may be based on an absolute difference of the means:– The RU must obtain values within ±25% of the

SU or within ± 0.05% of the mean value.

Dissolution

• Immediate Release:– A single 6 units dissolution test may be

sufficient

• Extended Release:– A 12 unit dissolution test or profile.

• For products with multiple strengths, bracketing may be appropriate.

Acceptance Criteria

• Results obtained from both laboratories should meet the dissolution specification for the product.

• May be based on the absolute difference of the means:– The RU should obtain values within ±5% of the

SU.

Identification

• Identification test can vary widely in complexity and techniques used. One determination is usually sufficient to demonstrate equivalence:– Retention Time (Assay)– Reference Factor (TLC)– Spectra (UV or IR)

Automated Methods

• The transfer of an automated or robotic method from one laboratory to another should focus on the ability of the equipment to generate equivalent and reproducible results with a minimum amount of carryover.

• If different automated system hardware manufacturers or different versions of software are being transferred, a complete revalidation is recommended

Automated Methods

• A strategy should be developed to deal with realistic laboratory workloads. Automated or robotics methods are used to analyze large numbers of samples and, therefore, the acceptance criteria should reflect the repetitive nature of this usage.

• There should be acceptance criteria for the maximum amount of sample carryover after analysis of an individual preparation and for a cumulative carryover after a series of sample preparation.

Automated Methods

• Example numbers of analysis for the cumulative carryover:– Assay: 6 sample preparations– Content Uniformity: 10 sample preparations– Dissolution: 6 sample preparations

• Blank sample preparations should be dispersed throughout a run to measure carryover.

Acceptance Criteria

• For individual and cumulative carryover should be very low (e.g. NMT 1.0%)*

• For equivalency the acceptance criteria should be the same as for manual methods.

*Based on the assumption that there is no carryover in a manual method.

Cleaning Verification

• When process validation has been achieved, cleaning verification becomes, intrinsically, a limit test.

• Analytical procedures may be transferred using replicate samples (spiked at levels of analysis both above and below the specification limit) and confirming both positive and negative outcomes.

Acceptance Criteria

• Spike levels should not deviate from the specification by an amount that is three (3) times the validated standard deviation of the analytical procedure, or 10% of the specification, whichever is the greater.

• All samples spiked above specification levels must demonstrate a failure to meet specification.

• Conversely, an appropriate fraction of the low-level spikes (e.g. 90% of the total) must demonstrate a passing result.

Microbiological Testing

• On-site validation approach is used for transferring qualitative and quantitative limit test:– Sterility– Antimicrobial Effectiveness– Microbial Contamination

• This approach involves validation of the procedure in each individual laboratory by executing a common validation protocol.

Microbiological Testing

• Since the purpose of such method validations is to demonstrate that, under test conditions, the method allows recovery of microorganism, both the SU and the RU should use identical techniques and materials, including inoculum preparation.

• It is recommended that each laboratory perform the validation in triplicate, utilizing different lots for each validation exercise, if possible.

Acceptance criteria

• Quantitative microbiological test should demonstrate recovery of test inoculum when compared to controls specified in the protocol.

Dose Delivery (include, but not limited to):

• Pressurized Metered Dose Inhalers (pMDI)

• Dry Powder Inhalers (DPI)

• Nasal Sprays

• Nebulizers– Dose Uniformity (USP<601>, EP 2.9.18)– Aerodynamic Particle Size

Particle Size

• Analytical Sieving– At least two (2) analyst at each laboratory

independently analyze three lots of material (where available) in triplicate.

– Protocols should include specific criteria of sieves, agitation method, and endpoint determination.

Acceptance Criteria

• Should include a comparison of the overall particle size distribution.

• Analysis of each test sample should meet product specification and the overall distribution pattern should be consistent between laboratories.

Particle Size Analyzers: Instrumental

• The transfer of a particle size method from one laboratory to another should focus on the ability of the individual analyzer to generate comparable results.

• If different equipment manufacturers or different versions of software are being transferred, a complete re-validation/qualification is recommended.

Acceptance Criteria

• Should include a comparison of the mass of drug recovered from the actuator, induction port, and individual collection vessels (e.g. plates).

• Total recoveries for each analysis should be between 85% and 115% of theoretical yield.

• Total drug recovered, mass median aerodynamic particle size (MMAD) and geometric standard deviation should be calculated and compared.

Alternate Approaches

• Perform re-validation of the method.

• Receiving Unit participation in the method validation.

• Other Approaches:– Number of analyst, samples, and distinct

executions of the method given in the guide are designated to demonstrate that the method(s) being transferred are reliable and robust.

Alternate Approaches

• The acceptance criteria stated throughout the guide are based on typical industry analytical procedures (e.g. HPLC, GC, UV).

• These example acceptance criteria are not intended to be universally applied to all methods and dosage forms.

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