Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry-Sayeh...

Sayeh MajzoobPharm. D., Ph. D. in Pharmaceutics; Pharma MBA

Email address: [email protected]: +98 912 1366744

Based on: ISPE Good Practice Guide-Technology Transfer-2003/2014 WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on

transfer of technology in pharmaceutical manufacturing Guideline for Technology Transfer-NIHS-Japan-2012 ICH Q10-Scale-up & Technology Transfer as a Part of Pharmaceutical Quality

Systems

19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 1

Understand scope and stages in technology transfer, and its successcriteria including:

Forming the transfer team and developing the project charter Consolidating knowledge for transfer and developing a technology

transfer proposal Identifying risks, conducting risk assessments and developing technology

transfer plan Executing the transfer Finalizing the transfer and performing the review Pitfalls


The ever-changing business strategies of pharmaceutical companies increasinglyinvolve intra- and inter-company transfers of technology for reasons such as theneed for:

Product life cycle (from R&D to pilot/clinical scale and Industrial scale) Increasing access to medicine with better prices (NGO initiatives/ Social Responsibility

) Additional capacity and freeing up capacity for new products Relocation of operations or consolidations and mergers Access to new markets on condition of Technology Transfer In-licensing Out-licensing Contract manufacturing


Research &development,

ClinicalPhases Scale-up

Post-approval

phaseProductionand launch

Scope of ISPE Technology transfer Guide

ISPE 2003/2014 and WHO Technical Report Series,No. 961, 2011)

The systematic [Step-by-step andplanned] procedure that is followed inorder to pass the documented knowledgeand experience gained during developmentand/or commercialization to an appropriate,responsible, and authorized party.

Technology transfer embodies both thetransfer of documentation AND thedemonstrated ability of a Receiving Unit toeffectively perform the critical elements oftransferred technology, to the satisfaction ofall parties and any, or all, applicableregulatory bodies.


ICH Q10- 3.1.2 The goal of technology transfer activities is to transfer product and

process knowledge between development and manufacturing, andwithin or between manufacturing sites to achieve productrealization. This knowledge forms the basis for the manufacturingprocess, control strategy, process validation approach and ongoingcontinual improvement.

Technology transfer (TT) comprises a science and risk-based principlesincluding: ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System ICH Q11 Development and Manufacture of Drug Substances (Chemical

Entities and Biotechnological/Biological Entities)

Transfer of technology requires a: Documented, planned approach using trained and knowledgeable

personnel working within a quality system, with documentation of datacovering all aspects of development, production and quality control.



Transfer of expertise and technology associated with: Analytical Methods APIs Dosage Forms

Useful from the earliest phases in a products life cycle through to, andincluding, post approval transfers

ISPE and WHO guides currently does not explicitly offer specific guidance related to biologicalproducts, blood related products, medical gasses, and medical devices.The concepts described therein are, however, broadly applicable and may be useful in theseareas as well.

Development and optimization are dynamic as they relate to the life cycle ofa product, process, or method, and as a result:

Development activities are expected to be adequately complete,for the specific stage in the life cycle, and appropriatelydocumented prior to initiation of transfer.

However, the baseline level of specifications or performance criteria mightprogressively improve (changes, variations, new methods, .).


If a Receiving Unit can routinely [consistently] reproduce the transferred product, process, ormethod against a predefined set of specifications as agreed with a Sending Unit and /or aDevelopment Unit, the transfer is considered successful.

Depending on the reason for the technology transfer, the criteria for success may vary,however, in all cases, because this work is in a regulated environment,documentation for the transfer effort is critical.

It is critical that a clear objective for any technology transfer project be developed.

It is also critical that a project team comprised of individuals from both the Sending Unit andthe Receiving Unit is established and that there is a precise understanding of each teammembers role and responsibility prior to initiation of the technology transfer project.


Skill alone will not ensure a successful technology transfer project.

Once a project has been identified and a team chosen, a clear and realistic projectimplementation, temporal plan is required to guide the project, manage expectations,and handle the inevitable deviations and changes that may present themselves duringimplementation.

Along with that plan comes the need to consider the temporal relationship betweenthe various tasks associated with a successful technology transfer.

It should be clearly understood that each technology transfer assignment is unique andit is, therefore, impossible to provide a generic technology transfer plan.


Effective Kick-off sessions so the team membersget to know each-other

Be friendly, positive, helpful, polite, fair, unbiased,flexible, professional and mature, understandingand empathetic

Teleconferences (TCs) Cellphone/Desktop apps such as Skype, IMO,

Telegram, Text messages, Whatsapp, . canexpedite many issues (though unofficial, viewthem as phone calls; Document and communicatethem officially immediately afterwards)


Group Emails for information only Keep the relevant people in the loop, and

the assistants/ substitutes in cc to follow-up in case the focal person is unavailable

If you want an email unanswered and tobe overlooked, address it directly tomore than 1 person!

Just pick up the phone Leave your desk and meet in person SharePoint Agendas Minutes of meetings Gantt charts (Excel, Word, MSP),

Pre-transfer Build transfer team and develop project charter (CEO/DIRECTORS level- estimates) Consolidate detailed knowledge for transfer and develop technology transfer protocol

(MANGERS level document-more in details and more accurate) Procurements/Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot

batches, Bio-batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database



Based on: ISPE Good Practice Guide-Technology Transfer-2003/2014 WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on

transfer of technology in pharmaceutical manufacturing Guideline for Technology Transfer-NIHS-Japan-2012 ICH Q10-Scale-up & Technology Transfer as a Part of Pharmaceutical

Quality Systems


(MANGERS level document-more in details and more accurate) Procurements/Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches,

Bio-batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database


Memorandum of Understanding (MoU) Very general 2 Bi-partite MoUs or 1 Tri-partite (inter- or Intra- sites) Name of products Scope Validity date Governing law (sometimes non-binding) .


General questionnaire (if applicable) Name/ Contact info/ Key persons and experience/

Company history/ Organization Chart Governmental/ Privately-owned/ Member of a

holding/ Possible contracts (Conflict of interests) Number of staff in each department: Manufacturing/ Packaging/

Warehouses/ QA/ QC/ Engineering/ IT,. (Ratios suitable based on thecompany operations/size)- Turnovers

Shifts/ Working Hours Dosage forms Cytotoxics/ Penicliins/ Cephalosporines/ Penems/

Sex hormones/ Biologics/ Herbal/ Live vaccines/hazardous.


In which activities are they willing to assist:Procurement, QC, Technical QC equipment: Types and Brands/ Models/ Numbers Stability Chambers, RoomsManufacturing/ Packaging technology: Types and

Brands/ Models/ Minimum and Maximum workingcapacities/ Numbers Facilities surface areas: Warehouses/ Manufacturing/

Packaging/ QC (Physicochemical, Microbiological) Engineering utilities: BMSs, EMSs, . QMS Certificates (GMP, ISO, Audits by international

companies,) Current and Pipe-line product list

Due Diligence Visits/ Audits Initially a visit by the focal person for smooth Audit planning An opening session, Site walking tour, Documentation review, Wrap-up Visit/ Audit reports and possible required CAPAS with timeline

Supply and Procurement/ Financial agreement 2 Bi-partite agreements or Tri-partite Transparent details of financial aspects and responsibilities in procurements, QC

tests/ Technical and Validation batches expenses/ Routine batch expenses


Technical and Qualityagreement

2 Bi-partite agreements or Tri-partite

Confidentiality agreement(CDA-NDA)


Pre-transfer

Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)

Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS leveldocument-more in details and more accurate)

Procurements/Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-batches,..

can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database


Setting focal persons in each party and having an introduction session (preferably face-to-face) Promoting project management skills, being organized, knowing the basics of modern

communication Clarifying responsibilities and authorities: no overlaps, gaps (RACI CHART, WBS) Emphasizing team-work spirit, keeping respective staff in the loop, not monopolizing, being fair,

fostering communication skills, no blame-shifting Encouraging open channels of communication: responding on time and willingly Considering language skills Choosing members based on technical knowledge of the process/ product: An experienced team Setting Channels of communication (Emails, TCs; Having required forms, templates, SOPs, WIs,

Flowcharts, Protocols) Team members not working as isolated islands, since timings and tasks are often very much

interrelated and intertwined


Microsoft WordDocument

Example of project charter (a high-level CEO/DIRECTORS document -estimates-using previous history): DIRECTORS SHOULD BE INFORMED OF THE GENERALITIES OFTHE PROJECT BEFOREHAND, AND THEY SHOULD SUPPORT IT!


Project name Approved by (Support by higher directors) Revision history Executive summary Goals Scope General Time-line and main milestones General risks (QRM):

to brief higher directors on the criticality andreasons behind decisions

Resources estimate (the Ms): Man Material Machinery Methods/Documents Money Management

General WBS (Responsibilities matrix)


Pre-transfer Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)

Consolidate detailed knowledge for transfer and develop technologytransfer protocol (MANAGERS level document-more in details and moreaccurate)

Procurements/Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-batches,.. can

be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database



APPROVALS (by all relevant key people) SUMMARY RESPONSIBILITIES (name the persons) REGULATORY TRAININGS NEEDED PRODUCTS AND ACTIVITIES TO BE TRANSFERRED HYGIENE SAFETY ENVIRONMENT PRODUCT/ PROCESS HISTORY REVIEW BEFORE

TRANSFER ANALYTICAL TRANSFER MANUFACTURING PROCESS TRANSFER (if applicable)

RAW MATERIAL AND SUPPLIERS PACKAGING MATERIAL (if applicable) STABILITY (If applicable) GAP ANALYSIS QRM (might be more detailed than the initial

QRM in the project charter) DOCUMENTS REQUIRED (SOPs, Protocols,

Checklists, Forms, Flowcharts, ) PLANNING (timelines) RELEASE/ APPROVAL CONDITIONS LOGISTICS


Gap analysis is Identification of all critical elements of a process/facility/staff which are available at the Sending Unit but are missing fromthe Receiving Unit, and to find and implement solutions for them.Receiving Unit readiness assessmentDemonstration runs; Technical batches; Media fillsProcessing/ Method GapsInformation-training-experience gapsFacility gaps


To achieve a higher assurance on qualityTo reduce the probability of failureTo systematically break down complex

processes and their possible failuresTo save time and resourcesTo facilitate and prioritize decision makingTo communicate critical points to all team

membersTo think critically about even simple

processes and gain in-depth knowledge ofeach, and their consequences


QRM (might be more detailed than theinitial QRM in the project charter);ICH Q9 Define stages and process flowchart Identify failure modes and their effects Root cause analysis: 5 whys, 2-Hs, Fish

bone diagram (Ishikawa), A3 problem-solving, PDCA, or other methods

Clear ranking basis FMEA, PHA, HACCP Listing current control measures Prioritizing failure modes Implementing CAPAs based on priorities;

Risk mitigation Final review and assessment

A history of the process including:The development and process rationale,justification of specification ranges, andprior validation activities, hold times, CPP,CQAs, Control strategies

Technology transfer protocol, whichcaptures the critical manufacturing processparameters

Technology transfer report templatedetailing the success (or failure) criteria andreport of the technology transfer

Batch record and Process Flow chartsand the relevant SOPs, Protocols, WIs,tips


Specifications and supplier list of material,machinery, equipment, reagents, size-parts...

Relevant Health, Safety and Environmentdocuments: MSDS of material,Containment and leakage measures

Transport validation protocol and reporttemplate (in case of transport of API,Bulks, Intermediates.)

Sometimes the Focal Unit or the Receiving Unit participate in preparation of these documents.

Sampling plans, Sampling techniques,

Frequencies, IPC and IPQC samplings

Methods of analysis and tips

Analytical transfer protocol

Stability study protocol and report

template

Cleaning instructions

Rework procedure


Required training documents

Artworks

Annual product review documentation

and template (include process capability,

process control trend summaries, and

process variations and the investigation

of those variations, follow-up actions,

and a rationale and summary of

reworked product)

General Technology Transfer Process description andFlowchart

Project Charter

Contracts

Project general and detailed time-line (Gantt charts, Pand inter-dependencies (Network Diagram)

Responsibility Matrix and Work Breakdown Structure(RACI CHART, WBS)

Audits and Visits and CAPA follow-up forms

Documents Transfer Receipt forms

Material Transfer Receipt forms


Training needs and records

QRM documents in technology transferprocess

Material/ Equipment procurement forms

Artworks and packaging material preparationSOPs

Regulatory processes SOPs

Minutes of meetings

Records of Technical batches

Lessons-learnt database

Sometimes the Sending Unit or the Receiving Unit participate in preparation of these documents:


Site VMP (at least parts which are relevant to the

Technology transfer project at hand)

Qualification documents of all relevant utilities,

machinery, equipment

QRM, PHA at the receiving site

Technology Transfer Validation Protocol and report

(both trouble-shooting trial technical runs and the

main runs)

Stability study report


Customized bi-lingual Batch Manufacturing and

Control Records and SOPs, WIs, Forms, (both for

trouble-shooting trial technical runs and the main

runs)

Deviations and Change control documents

PQR

Cleaning validation documents, taking into account

the transferred products

Sample retention

Local Dossier (if relevant)


(MANGERS level document-more in details and more accurate) Procurements/ Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches,



The suppliers list and detailed specifications of all required APIs, Excipients,Components, Packaging material, Reagents, QC Supplies . should be provided bythe Sending UnitThe criticality of using the exact same suppliers should be communicated with

the Receiving UnitIt should be noted that sometimes all of the critical attributes might NOT be

included in the CoA or Specification sheet or DossierIn case of inability of the Receiving Unit to procure the required item (with

reasonable price and in a timely manner), the Sending Unit might facilitate itssupplyIn case the same suppliers are not used, the vendor selection procedure should

be followed


!A Certain micronized purified API is exclusively supplied by the innovatorcompany, affecting dissolution, absorption and efficacy of the product

A certain Ethanol grade is solely manufactured by one American Company,exclusively for one customer

A certain PVC grade with low Water Vapor Transmission Rate (WVTR) is to beused by the Receiving Unit for packaging, while due to local production of PVC,imports of PVC is banned

Imports of a certain specific HPLC column or UV spectrophotometer cell-holder/spacer, takes 5 months and double the real price, delaying the analyticaltransfer and making it very expensive


Pre-transfer Build transfer team and develop project charter (CEO/DIRECTORS level- estimates) Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS level

document-more in details and more accurate) Procurements/Supplies

Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-

batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database


Authorizations (both for finished product and imported material, .) and Data-matrix codes(traceability), such as providing DIAFs (Drug Importing Application Form), CPPs (Certificate ofPharmaceutical Product), legalized documents, for the intermediate productsArtworks managementStability studies (what are accepted as commitment studies, which time points,)SUPAC and Dossier variationsSampling plansProduct registration at different stagesManufacturing and analysis change control and variationsBatch recordsLocal Dossier compilation (if relevant)Complaints, Retained samples, Pharmacovigilance, PQR .Other Documentations


Pre-transfer Build transfer team and develop project charter (CEO/DIRECTORS level- estimates) Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS level

document-more in details and more accurate) Procurements/Supplies Regulatory

Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage of transfer, Pivot batches, Bio-

batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database


Gap and risk analysis in trainings should be done in the Receiving Unit with a view fordetermining organizational shortfalls, and correcting them:Project management capabilityTeam-work ability, and culture and habitsGMP-compliant behavior, regulatory and safety issues, current state of product-related

process understanding, manufacturing processes, documents, analytical methods,equipment, plant capabilitiesLanguage skillsNovel technologies (communications, IT, .)

Trainings should be assessed and documentedHands-on experience/ Visit to Sending Unit should be arranged if necessary


Can be regarded as training and confidence-gaining opportunity for the transfer teamCan prevent waist of precious, and sometimes expensive materialSaves time and decreases the chances of failure in Validation/Qualification batches/ runsAllows modifying several affecting parameters in a wide range to gain a better view of the design space

(particularly in case of scale-ups, batch-size changes, different machinery/technology in SU and RU)Allows some overlooked and unidentified issues/risks to surfaceAllows different processes in the process train to be assessed individually, with less time and continuity

constraintAllows customization of batch records, documents . to be more adapted to the real processCan also be regarded as PQ of machinery

Sometimes placebo materials are used, and sometimes the exact original material


Using placebo powders for tablet manufacturing, coating packaging

Using placebo solutions in aseptic filling

Using trial runs in dissolution and HPLC tests, before the official analyticaltransfer



(MANGERS level document-more in details and more accurate) Procurements/Supplies Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation (depending on the stage

of transfer, Exhibit, Bio-batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up Lessons-learned knowledge database


Lab-scale: 1001000 times less than production scale Formulation and packaging development, Early clinical and/or preclinical stages. CQAs

Pilot batches-Scale-up batches: Process-development or optimization stage Preclinical and mid- to later-stage clinical

evaluation Formal stability studies If supporting formal registration, size at

least 10% of the production-scale batch or100,000 units, whichever is greater


Exhibit batches-Qualification batches: In the manufacturing plant or the

plant with similar equipment For process qualifications For stability studies The reason Exhibit batches are used

by pharma/biopharma companies tosave time and money

Hold time studies, change ofparameters within design space

Biobatch-Pivotal batch: The size of the biobatch adequate to represent the production batch size, and with production machinery i.e.

no scale up beyond ten times. Scale up beyond ten times should be supported with a new biobatch/BW data to support the new size

(possible exception for low-risk cases if well-defined). A biobatch should be the greater of 100,000 units, or not less than 1/10th the proposed production size. A biobatch of < 100,000 units may be accepted, but then no scale-up is allowed. This should be clearly

indicated in reports for the product, as it affects allowable variations.

Validation batchesThe actual size and parameters and machinery

Commercial batches


At successful completion of all previous tasks, the Process/ProcedureValidation Batches/Runs, can take place.

While it may be valuable to have personnel present from the SendingUnit, it is critical that the Receiving Unit actually execute the study(i.e., operate the equipment, take the samples, perform the testing,etc.) so that the study is truly representative of what will occur at thesite post-validation.

The validation report should then be completed by the receiving site.


Documentation of all observation (even those out of scope of ValidationProtocol);

Constant precise observation even of the minute details Note-taking and Photographing, Video filming and any measure to help

future review of events Trying to resolve any issue with minimum modification to the previously-

approved protocol In case of need for change during the validation runs, it needs to be first

discussed and approved by relevant authorities In setting of parameters within the agreed ranges or in case of need for

change, try to modify one parameter at a time to be able to assess theeffects of individual parameters.


Best practices:Plan extra runsPrepare for deviations & conduct in controlapprovals

Follow in-process results closely19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 55

Know your process

Understand your variability

Build a Control Strategy early

Establish a lifecycle


Revisit your Risk Assessment

Monitor the process andanalyze your results

Continued processimprovement will lead you tothe Future!

The completed Validation Report should bereviewed against the previously setAcceptance Criteria and Objectives (bySending Unit and/or the Focal TechnologyTransfer Unit).In case of failure in these runs, an official

Documented Root Cause Analysis should beconducted.The required steps should be modified

(having in mind a Risk Assessment concept),in a documented and controlled manner, withthe involvement of all parties.


The technical runs can be repeated toassist in RCA The validation runs then should berepeated, until it can be concluded thatthe Process/ Product/Technology issuccessfully transferred:

Assures consistency ofmanufacturingReproducibility of process designevaluated commerciallyProvides assurance of commercialreadiness

At this stage the Project can be often wrapped up.

! In most cases some minor non-critical issues will remain, which needCAPAs and follow ups for continuous improvement.

The Sending Unit might still remain in contact with Receiving Unit to assist in: Continuous process verification (3-stage process validation approach) Control strategy Ongoing assurance process is in control Trending/Statistical Analysis/Proactive Improvement




Bio-batches,.. can be included) Perform review Need to repeat any step Finalize transfer and Wrap-up

Lessons-learned knowledge database19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 60


Review the deliverables vs. plan

Review budget vs. plan

Review timeline vs plan

Revise templates/documents accordingly

Questionnaire to gather information

Group meetings to finalize the output(Issue(s) faced within the project or the team)

What did you chose to do about the issueand why?

What was done well/not done well?

Why do you think things went well/did notgo well?


What should be done similarly next time?What could be improved next time?Are there any generalizable LLs to be gained

from this experience? Are there any

generalizable LLs to be gained from this

experience?

GapsList actionable LLsKey words:

(for archiving purposes)

Differing technologies, machinery, control parameters

Underestimating or overlooking analytical methods transfer

No complete review of project charter by Top directors, leading to delays and lack oftimely support by them

Lack or inefficiency of Quality Management Systems in any of the parties involved

No proper development and validation of the case in the Sending Unit

Overlooking trainings

Differing batch sizes


Differing excipient/ packaging material suppliers

Language/ communication gaps and non-responsive and non-open channels; No face-facevisits, Lack of transparency

Lack of project management skills and human resources skills and technical skills in focalpersons

Not considering plan Bs for changes outside of ones control area

Lack of precise observation and documentation habits

Unrealistic time-lines and commitments, leading to rush and subpar performance at the finalstages19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 66

Based on USP 39 (Since USP 35-2012) Transfer of Analytical procedures

USP 39 Analytical Data-Interpretation and treatment WHO Technical Report Series, No. 961, 2011, Annex 7, WHO guidelines on transfer of

technology in pharmaceutical manufacturing


Sayeh MajzoobPharm. D., Ph. D. in Pharmaceutics; Pharma MBA

Email address: [email protected]: +98 912 1366744

Analytical transfer:What is it, why should it be done? Definitions Is it required to officially perform Analytical Method Transfer: FDA warning lettersScope: In what situations might we need Analytical Method Transfer?Method Validation? Method Verification? Method Transfer?Types of Analytical Method Transfer: A risk-based approach-How it is done? :Comparative testingCo-validationRe-validation-Partial Revalidation/VerificationTransfer waiver

Some possible designs of Analytical Method transferAcceptance criteria, Comparative testing, Statistical tests



Steps in Analytical Method TransferPre-transfer:Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERS level

document-more in details and more accurate)RegulatoryTrainingsTechnical/Trouble shooting batches/runsProcess/Procedure qualification/validationPerform reviewNeed to repeat any step (non-conformance remedial action)Finalize transfer and Wrap-upLessons-learned knowledge database

Case-study of an analytical transferPitfalls and possible reasons for failure in Analytical Method Transfer

USP 39 (Since USP 35-2012) Analytical transfer is the documented process that qualifies a

laboratory (the receiving unit) to use an analytical test

procedure that originated in another laboratory (the

transferring unit), thus ensuring that the receiving unit has the

procedural knowledge and ability to perform the transferred

analytical procedure as intended*.

*(Under actual conditions of use)19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 70

The firm failed to perform finished product test method transfers for 34products (W-187)

The firm has failed to perform method validations, method verifications, ormethod transfers for any of the laboratory test methods used to test activepharmaceutical ingredients (W-187)

Failure to establish and document the accuracy and reproducibility of testmethods employed. (W-186)

For example, methods that were validated at one facility and transferred toxxx site are being used without a methods transfer or revalidation protocol.(W-186)


Sponsor company Contract labAnalytical development QC labsAcross different sites

The same lab conditions Different lab conditions

Existing instrumentation New instrumentation With different specifications With different technology

Supplier of material ClientTransfer to new instruments with different instrument characteristics


For: APIs Excipients Finished Products Intermediates IPQC samples Packaging material Stability samples Cleaning validation analytical methods


Method Transfers are closely related to Validation/ VerificationMore challenging: multiple laboratories and companies involved; comparison

and assessment of equivalence is the goal:Different approaches to Validation/ Verification and TransferDifferent expectations of what is an acceptable Validation/ TransferDifferent instruments and facilitiesThe method should be adequately validated at the Sending Unit prior

to transferBalancing Act

Adapt method to new facility/instrumentMeet new facility validation requirementsMaintain validated state of method

Typically Analytical Method Transfers are mostly concerned with Accuracy and Precision(assuming the method should be validated at the sending unit).


Based on a risk assessment taking into account the complexity and criticality of theanalytical procedure and its purpose, as well as the experience and knowledge of the SUor RU.

Comparative Testing (with appropriate justifications) - Analysis onsamples, from the same lot, by both laboratories and acceptance

criteria is met.

The acceptance criteria and variability are outlined in a transferprotocol.


Co-validation of Laboratories- The transferring laboratory works with the receiving laboratory inan inter-laboratory validation effort at the transfer laboratory site. An assessment conducted,

using a transfer protocol, to evaluate the reproducibility of the process.

Receiving lab is part of original method validationTransferring and receiving lab conduct the same validation experimentsUseful for methods not (fully) validatedMust be based on pre-approved validation protocols and acceptance criteriaShould challenge all USP or ICH validation parametersInclude receiving lab in validation through inter-laboratory tests.Ensures harmonization of method at both sites


Revalidation/Partial Revalidation- Complete or partial method validationper Validation of Compendial Procedures by the receivinglaboratory:

Mostly when the transferring labis not available or participating


Transfer waiver- Under certain circumstances, without comparison and generation ofinter-laboratory comparative data.Some scenarios that may justify the waiver:The new product's composition is comparable to that of an existing product

and/or the concentration of active ingredient is similar to that of an existingproduct and is analyzed by procedures with which the receiving unit already hasexperience.The analytical procedure being transferred is described in the USP-NF, and is

unchanged. Verification can apply in this case (see ).The analytical procedure transferred is the same as or very similar to a

procedure already in use.The personnel/[equipment] in charge of the development, validation, or routine

analysis of the product at the transferring unit are moved to the receiving unit.

If eligible for transfer waiver, the receiving unit should document it.


Some basic compendial procedures including, but not limited to: Loss on drying Residue on ignition Various wet chemical procedures such as acid value Simple instrumental determinations such as pH measurements

However, for the application of already established routine procedures to compendialarticles tested for the first time, it is recommended that consideration be given to anynew or different sample handling or solution preparation requirements.


Sample preparation and sample handling are the most critical issues and most commonreason for failure of method transfer.

Based on the intended use of method the samples can be:Routine samples Expired Spiked samples Forced degradation samples Stability samples IPQC samples Intermediate products

Trainings:Picture and video-based training- Face to face training and meetings (language barrier: can points be

transferred in detail? Specialized translation)Tips (Formulation dependent,), expertise, experienceDetails of equipment, material, reagents, to be disclosed


As the dossier does not disclose the QC details, so some Closed part info. might berequested. The following data might be beneficial to be shared by the Sending UnitDevelopment data, SST results, unusual and OOS resultsHistory of critical analytical data (e.g., release and stability data) and rationale for proposed

specificationsStability results and tests are an excellent source to evaluate the real routine performance of an

analytical procedure

If needed, change control and regulatory implications should be addressed.

The analytical transfer should be made "Under actual conditions of use in the ReceivingLab.

In some contexts, the main responsibility might be with RU, due to more experience withthe Product type or Test or Transfer.


For older products it is recommended that analytical methods for stability arealso reviewed for adequacy at the time of transfer and agreed on.

The choice of particular strategy needs justification.

The type of transfer is defined for each method based on a risk assessmenttaking the complexity and criticality of the analytical procedure and its purposeinto account as well as the experience and knowledge of the RU.

Possibility of a waiver

Microbiological and Biological methods?19-Nov-16 Technology Transfer and Under-License Manufacturing in Pharmaceutical Industry- Sayeh Majzoob 82

Setting acceptance limits/ criteria: Somewhat challenging and daunting task

Types of comparisons: Direct comparison of mean values based on

common industry practice (a priori) for each type oftest (Precision and Accuracy)

!But with direct comparison, the number ofrepetition and variability are overlooked

(Schuirmanns) Two one-sided t-test (TOST) (Notstudents t-test)


USP 39ANALYTICAL DATA-INTERPRETATION AND TREATMENT COMPARISON OF ANALYTICAL PROCEDURES

APPENDIX F: EQUIVALENCE TESTING AND TOST Classical statistical hypothesis testing:e.g.: The null: Two means are equal.

The alternative: Two means differ.The null hypothesis will rejected in favor of the alternative if the evidence is sufficient against the null.

A common error is to interpret failure to reject the null as evidence thatthe null is true.

Actually, failure to reject the null just means the evidence against the null was notsufficient.

For example, the procedure used could have been too variable or the number ofdeterminations too small.


"Null Until Proven Alternative" Look at it in terms of "innocent until proven guilty" in a courtroom:

As the person analyzing data, you are the judge. The hypothesis testis the trial, and the null hypothesis is the defendant. The alternativehypothesis is like the prosecution, which needs to make itscase beyond a reasonable doubt (say, with 95% certainty).

If the evidence presented doesn't prove the defendant is guiltybeyond a reasonable doubt, you still have not proved that thedefendant is innocent. But based on the evidence, you can't rejectthat possibility.

So how would that verdict be announced? It enters the court recordas "Not guilty."


Therefore: To demonstrate similarity, (such as results from two laboratories), thenthe similarity should be set as the alternative hypothesis (not thedifference).

A statistical test for an alternative hypothesis of similarity is referred to as anEQUIVALENCE TEST.

It is important to understand that:"equivalence" does not mean "equality."

Equivalence should be understood as "sufficiently similar" for the purposes ofthe laboratory(ies).

As noted earlier in this chapter, how close is close enough, is something to be decideda priori.


Accuracy and precision comparison:

Comparison of the accuracy in two labs (USP

The lower and upper limits of the confidence interval onlyshow how large the true difference between the twoprocedures may be, not whether this difference is consid-ered tolerable.

Such an assessment can be made only within theappropriate scientific context. This approach is oftenreferred to as TOST (two one-sided tests; USP39ANALYTICAL DATA-INTERPRETATION ANDTREATMENT: see Appendix F)


Possible reasons of False Significance or Non-significance if the difference inaverages is caused by applying simple T-tests:! A statistically significant difference may not be large enough tohave practical importance to the laboratory because: It may have arisen as a result of highly precise data or a larger sample size.

! On the other hand, it is possible that no statistically significantdifference is found, and yet an important practical difference cannotbe ruled out.This might occur, for example, if the data are highly variable or the sample size is too

small.

Thus, while the outcome of the t-test indicates whether or not a statisticallysignificant difference has been observed, it is not informative with regard to thepresence or absence of a difference of practical importance.


Pre-transfer: Build transfer team and develop project charter (CEO/DIRECTORS level- estimates) Consolidate detailed knowledge for transfer and develop technology transfer protocol

(MANGERS level document-more in details and more accurate) Regulatory Trainings Technical/Trouble shooting batches/runs Process/Procedure qualification/validation Perform review Need to repeat any step (non-conformance remedial action) Finalize transfer and Wrap-up Lessons-learned knowledge database



Pre-transfer: MoU-Questionnaire-Audits-Visits-Detailed Contracts

Build transfer team and develop project charter (CEO/DIRECTORS level- estimates)

Consolidate detailed knowledge for transfer and develop technology transfer protocol (MANGERSlevel document-more in details and more accurate):

Tips-Details-Previous method development data-Key analysts-Sample storage and handlings-MSDS-Safety points-Equipment comparison-Gap analysis-QRM-CAPAs

Procurements/Supplies: Samples (Stability indicating: Expired-Forced degradation-Spiked)-Packaging material tests-

Reference Standards-Columns-Cells, Spacers, Reagents-Solvents

RESPONSIBILITIESThe primary tasks of the Sending Unit are:Create the Transfer ProtocolExecute TrainingAssist in AnalysisAcceptance Criteria

The Receiving Unit provides:Qualified InstrumentationPersonnelSystemsExecutes the Protocol

The Sending Unit and the Receiving Unit are jointlyresponsible for issuing the final report.


Regulatory: Do the transfer strategy and QRM meet regulatory approval? Any variations compared to dossier-Is the receiving Lab accredited .

Trainings: Transparent-Face to face-Tips-Pictures-Videos-Visit to the Sending lab

Technical/Trouble shooting batches/runs: As not to waste resources, to be clearly oriented Trial runs and pose any questions/ambiguity to the Sending Laboratory

Process/Procedure qualification/validationPerform reviewNeed to repeat any step (non-conformance remedial action)Finalize transfer and Wrap-upLessons-learned knowledge database


AnalyticalTransfer Protocolshould include:


Analytical transferreport form template tobe included forharmonization


Unrealistic risk assessment of the complexity and criticality of the method, and thetwo labs involvedChoosing un-scientific acceptance criteria and acceptance intervalDifferent equipment, in-experienced analysts and lab environmentMaterials/ Reagents/ Accessories from difficult-to-purchase suppliers (Columns,

Special grade reagents,)Lack of Robustness and Reproducibility of method; Lack of full validationLack of documented and verified detailsNo open and responsive communication channel


Understand technology transfer and success criteria including:Forming the transfer team and developing the charterConsolidating knowledge for transfer and developing a technology

transfer proposalIdentifying risks, conducting a risk assessments and developing

technology transfer planExecuting the transferDeveloping the process (procedure) qualificationFinalizing the transfer and performing the reviewDeveloping an effective process for Technology Transfer including the

exchange of knowledge between the sending unit and the receivingunit for drug substance, drug product and analytical procedures.Pitfalls


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