basic principles of gmp - whomodule 14 | slide 19 of 31 2013 transfer of technology actions may...

Module 14 | Slide 1 of 31 2013

Basic Principles of GMPBasic Principles of GMP

Transfer

Of

Technology

Part 2

Annex 7. TRS 961, 2011


Transfer of TechnologyTransfer of Technology

Production:

Processing, packaging and cleaning



Production - Processing, packaging and cleaning

Principles:

� RU able to accommodate the intended production

capacity

� Single-batch manufacture, continuous production or

campaigns.

� Identify technical expertise, site technology and site

capabilities of RU 5.1 – 5.3



Processing

Starting materials

� Same specifications / relevant functional characteristics – SU and

RU

� Ensure properties the same where these may influence the

process or product

5.5



Active pharmaceutical ingredients (API)

� open (applicant’s) part of APIMF/DMF or equivalent information

� manufacturer and associated supply chain

� step of the API to be transferred

� flow chart of synthesis pathway, outlining the process, including

entry points for raw materials, critical steps, process controls and

intermediates

� Information on physical form e.g. photomicrographs, polymorphic

and solvate forms

– solubility profile; pH in solution …/25.6



� intrinsic dissolution rate

� particle size and distribution

� bulk physical properties (e.g. bulk and tap density)

� water content

� microbiological considerations (including sterility, bacterial

endotoxins and bioburden)

� specifications and justification for release and end-of-life limits

� summary of stability studies and retest date …/3

5.6



� observed synthetic impurities

� information on degradants

� potency factor

� storage and or handling (e.g. sensitivity to heat, light or moisture)

5.6



Excipients

� manufacturer and associated supply chain

� description of functionality

� definitive form (particularly for solid and inhaled dosage forms)

� solubility profile (particularly for inhaled and transdermal dosage

forms)

� partition coefficient, including the method of determination (for

transdermal dosage forms)

� dissolution rate

5.7



� particle size and distribution

� bulk physical properties; compaction properties (for solid dosage

forms)

� melting point range (for semi-solid or topical dosage forms)

� pH range (for parenteral, semi-solid or topical, liquid and

transdermal dosage forms)

� microbiological considerations

� specifications and justification for release and end-of-life limits;

� storage and or handling5.7



� ionic strength (for parenteral dosage forms)

� specific density or gravity (for parenteral, semi-solid or topical,

liquid and transdermal dosage forms)

� viscosity and or viscoelasticity (for parenteral, semi-solid or

topical, liquid and transdermal dosage forms)

� osmolarity (for parenteral dosage forms)

� water content (for solid and inhaled dosage forms)

� moisture content range (for parenteral, semisolid or topical, liquid

and transdermal dosage forms) 5.7



Provide detailed characterization of the product

� Qualitative and quantitative composition

� Physical description

� Method of manufacture

� In-process controls

� Control method and specifications

5.8



Provide detailed characterization of the product

� Packaging components and configurations

� Safety and handling considerations

� History of process development – helps with further development

and or process optimization after successful transfer

5.8



Development information

� Clinical development

– route and form selection,

– technology selection, equipment, clinical tests, and product

composition;

– Scale-up activities

– process optimization,

– statistical optimization of critical process parameters,

– critical quality attributes

– Pilot report and pilot-scale development activities5.9



Development information (2)

� Full-scale development activities

– number and disposition of batches manufactured

– deviation and change control

� Change history and reasons

� Investigations of problems and the outcomes of the

investigations5.9



Current processing and testing information to be

provided by the SU

� Health, safety and environmental issues

� Detailed description of facility requirements and equipment

� Information on starting materials, applicable MSDS

� Storage requirements for raw materials and finished products

� Description of manufacturing steps and analytical methods

– narrative and process maps or flow charts, and or master batch

records, in-process hold times and conditions, order and method of

raw material addition and bulk transfers between processing steps

5.10 – 5.11



Current processing and testing information to be

provided by the SU

� Identification and justification of control strategy

– critical performance aspects

– process control points

– product quality attributes

– statistical process control (SPC) charts

� Validation plans and reports

� PQR; stability information; environmental conditions 5.11



� Location of all equipment considered

– process maps or flow charts

� Flows of personnel and material

� Impact of introducing a new product

� Modification of existing equipment documented in the transfer

project plan

� RU compare own with that of SU - including qualification

� Gap analysis

� Must be able to reproduce the process (volumes and batch sizes)

5.11



During transfer process

� Identify and understand any differences in facilities, systems and

capabilities

Actions may include:

� comparison and assessment of suitability and qualification of

facility and equipment;

� description of manufacturing process and flow of personnel and of

materials5.12



Actions may include (2):

� determination of critical steps in manufacture

– also hold times, endpoints, sampling points and sampling

techniques

� writing and approval of SOPs

� evaluation of stability information

– Generate site-specific stability data

� compliance with regulatory requirements for any changes made,

e.g. in terms of batch size 5.12



Packaging

Same procedure/principles as those of the production and include:

� specifications for a suitable container or closure system

� additional information on design, packing, processing or labelling

requirements

� tamper-evident and anti-counterfeiting measures

� specifications for QC testing – also drawings, artwork and material

(e.g. glass, card) 5.13 – 5.15



� Based on the information provided, the RU should perform a suitability study for initial qualification of the packaging components.

� Other considerations in packaging:

– to provide adequate protection (preventing degradation of the

medicine due to environmental influences)

– Should be safe (absence of undesirable substances released

into the product)

– Compatibility (absence of interaction possibly affecting

medicine quality)

– Performance (functionality in terms of drug delivery)5.16



Cleaning



Cleaning - Key messages

� Prevention of contamination and cross contamination essential

� Manufacturing process, operator exposure, environmental effects

� Limits for product residues

� Rationale for limit selection

� Site SOPs developed and validated based on e.g.:

– potency, toxicity, solubility, corrosiveness, temperature sensitivity,

manufacturing equipment design and configuration, cleaning agent

and product residue 5.17 – 5.18



Adequate cleaning procedures are essential

� Cleaning procedures and their validation are site-specific

� Know:

– information on solubility of active ingredients, excipients and

vehicles

– minimum therapeutic doses of active ingredients

– therapeutic category and toxicological assessment

– existing cleaning procedures

5.18



Adequate cleaning procedures

� SU to provide

– cleaning validation reports

– chemical and microbiological

– Information on cleaning agents used

– Efficacy

– Not interfere with analytical testing for residues of APIs

– Information on recovery studies to validate the sampling

methodology5.18



Documentation

� Wide range of documents needed to support transfer

� Documented evidence for successful transfer

� Technology transfer summary report:

– the scope of the transfer,

– the critical parameters as obtained in the SU and RU

(tabulated)

– final conclusions

� Discrepancies and actions taken listed8.1 – 8.2



Examples

Key Task Document from SU Transfer document

Equipment selection

and transfer

List of equipment,

systems, makes and

models, qualification

Drawings, manuals

Side by side

comparison

Gap analysis

Qualification



Examples


Process transfer: Production

and packaging

Reference batches

Development reports

Specifications

Validation

DMF

BMRs

BPRs

Stability

Deviations

PQR

History of development

Experiences

Provisional BMD

Provisional BPD

Process validation



Examples


Cleaning SOPs and Validation SOPs

Cleaning validation

protocol and report



Summary

� SU and RU - responsibilities

� Regulatory requirements

� Transfer: Organized and managed

� Premises, Equipment, Materials, Documentation, Personnel

� Data and information – protocols and reports

� Production and Quality control

� Include qualification and validation



� Case study and/or assessment

basic principles of gmp - whomodule 14 | slide 19 of 31 2013 transfer of technology actions may...

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