good laboratory practice in the research and development lab

8/14/2019 Good Laboratory Practice in the Research and Development Lab

1/7

19 Good Laboratory Practice in

the Research and DevelopmentLaboratory

ALASDAIR J. SHEPHERD

19.1 INTRODUCTION

The paramount consideration in the design and manufacture of an agent formedicinal use is to ensure that the production process is both safe andcontrolled. Two codes of practice have been developed to ensure conformityto these requirements: Good Manufacturing Practice (GMP) and Good Lab-oratory Practice (GLP). The basic principles of these codes of practice arediscussed briefly below.

19.2 GOOD MANUFACTURING PRACTICE

In the UK Medicines Control AgencysRules and Guidance for PharmaceuticalManufacturers (1993) it is stated that the majority of reported defective med-icinal products resulted from human error or carelessness. In order to pre-vent or limit the occurrence of such errors, a system of controls with empha-sis on hierarchical testing and documentation (GMP) has been developed for

the manufacture of medicinal products, including biologics. The main com-ponents of GMP comprise controls of both production and quality. Produc-tion control is concerned with manufacturing, including the suitability of thefacility and staff for manufacture development of standard operating pro-cedures (SOPs) and record keeping. Quality control is concerned with samp-ling, specifications and testing, and with documentation and release pro-cedures, ensuring satisfactory quality.

Gene Therapy Technologies, Applications and Regulations. Edited by A. Meager 1999 John Wiley & Sons Ltd

Gene Therapy Technologies, Applications and Regulations.Edited by Anthony MeagerCopyright 1999 John Wiley & Sons Ltd

Print ISBN 0-471-976709-2 Electronic ISBN 0-470-84238-5


2/7

19.3 GOOD LABORATORY PRACTICE

The testing referred to above is conducted according to Good Laboratory

Practice (GLP), which assures the quality and validity of the data generated(Department of Health, 1989, 1997; Food and Drug Administration, 1997).GLP is regulated by the Department of Health in the UK, where it is definedas the organisational processes and the conditions under which laboratorystudies are planned, performed, monitored, recorded and reported (Depart-ment of Health, 1989).

Compliance with GMP and GLP guidelines requires monitoring by de-fined quality assurance staff operating independently of personnel involvedin manufacturing or testing. Clearly the implementation of such standards

for early phase clinical trial material is a costly procedure. This is of concernto many academic groups, which are being funded to conduct time consum-ing research into gene therapy delivery systems for use in clinical protocols.There is a necessity to ensure that potential therapies based on viral vectorgene delivery systems enter clinical trials in a timely and cost effectivemanner without, however, compromising the safety and quality of the agentadministered. This is a difficult balance to achieve as the control and safety ofthe cell lines and of the production process for viral vector stocks is para-mount for a product that is subjected to, at best, minimal purification.

Compliance with GMP and GLP standards is the optimum for productionof a medicinal product and these standards should therefore be appliedwhenever possible. The investment in terms of time and cost in attaining suchquality standards and safety controls in a clinical protocol is a wise long-termstrategy, which could prevent unforeseen contamination of a novel genetherapy agent (Smithet al., 1996). While it is evident that GMP applies to theindustrial production process and GLP to testing associated with the process,the manner in which the product may have been developed initially hashistorically been less controlled. Biopharmaceutical products may begin

development either in academic or industrial research laboratories, whererequirements to comply with such regulations are lacking. GLP regulations inboth the European Union (EU) and the USA pertain specifically to non-clinical laboratory studies to determine the safety of test substances (Depart-ment of Health, 1997; Food and Drug Administration, 1997). However, thereis recognition in industry, accompanied by increasing pressure from regula-tory bodies, that processes should be controlled at as early a stage in develop-ment as possible. In academia, also, there is heightened awareness of the needfor research and development to be conducted to standards that will be

acceptable to retrospective regulatory scrutiny. While simple adoption of fullGLP compliance for such studies would be the ideal, there are a number offactors which render such a course difficult for many laboratories, the mostimportant of which is financial. GLP requires an independent quality assur-

GENE THERAPY TECHNOLOGIES, APPLICATIONS AND REGULATIONS376


3/7

ance unit, the prime responsibility of which is to ensure that studies areperformed in accordance with GLP principles. Provision of the specificpersonnel and resources, including time, which require to be allotted to this

function is problematic for academic laboratories in particular.Thus, while adoption of the principles of GLP remains a standard which

may not be applicable to research and development, it is nevertheless poss-ible and desirable to incorporate many of the tenets of GLP into earlydevelopment programmes. The principal features of GLP which should beadopted into the research and development laboratory are: (i) traceability ofreagents and materials, (ii) adherence to written protocols (SOPs) and studyprotocols (SPs) where possible, and (iii) designation of personnel (studydirectors) with responsibility for defined aspects of studies. This chapter sets

out the principal considerations in order to achieve standards of qualityassurance in accordance with the principles of GLP for each of the aboveaspects. In addition, it seeks to address the role and function of qualityassurance in relation to research and development.

19.4 RESPONSIBILITY

The overall responsibility for ensuring that the principles of GLP are com-plied with for any facility, industrial or academic, rests with the designatedmanagement (Department of Health, 1997). The principal duties of manage-ment are to ensure that appropriate personnel, facilities, equipment andmaterials are available, that appropriate documentation is implemented andarchived and that there is a quality assurance programme with designatedpersonnel. In addition, management should designate an appropriatelyqualified and trained individual as study director.

19.5 TRACEABILITY

It is important that all reagents and materials used during research anddevelopment are of optimal quality and free from contamination. Materialsshould be obtained from sources where documentation exists regarding theacceptability of the reagent in relation to defined criteria. Documentaryverification of the specifications of most materials and reagents is providedby the manufacturer in the form of a certificate of analysis (C of A), which

will apply to each lot or batch.For cell cultures, important aspects to be documented include source,

passage history and manipulations, media (including raw materials of ani-mal origin), potential exposure to contaminating agents and the degree of

GLP IN THE RESEARCH AND DEVELOPMENT LABORATORY 377


4/7

testing to determine freedom from contamination. Where possible, cell lines,antibodies or infectious agents should be obtained from recognised reposito-ries such as the American Type Culture Collection (ATCC) or the European

Collection of Animal Cell Cultures (ECACC). For primary cell culturesderived from humans, it is important that information on the health status ofthe donor is obtained, particularly with regard to infectious viruses. Similarconsiderations should apply for primary cultures derived from animals.Where necessary, additional testing of cell cultures or virus stocks should beperformed to ensure freedom from contamination with agents which couldcompromise the safety of operators or the product.

Raw materials of animal origin which may be used in cell culture includefoetal bovine serum and porcine trypsin, both of which may be contaminated

with viruses (McLeanet al., 1997). Manufacturers C of As for such materialsshould contain results of assays for viral contamination in addition to otherspecifications. It is important that bovine serum is sourced from countrieswithout endemic bovine spongiform encephalopathy (BSE). Reagents ofhuman origin (for example those derived from human blood) should beaccompanied by adequate information regarding the health status of thedonors. Supplementary testing should be performed where appropriate.

For key raw materials, documentation received should be verified by auditinvestigation to confirm that the information provided accurately represents

the suppliers procedures and that the process for certification is adequate.Such an audit should be performed before use of the material. The results ofthe audit should be used not only as the basis for acceptability, but also todetermine whether supplementary testing of the material should be per-formed.

Each batch, lot or individual item used in research and developmentshould be allotted a unique material receipt, or receiving number, andshould be labelled accordingly. Labels should also record information suchas storage conditions and expiry dates.

It is important to consider the environment in which development andmanipulations are performed. Other work being performed in the samelaboratory may present the possibility of cross-contamination of cell lines orof contamination with infectious agents. Particular attention should be givento storage of reagents, working samples and stocks in order to avoid cross-contamination. Storage of materials in liquid nitrogen Dewars, freezers andfridges should be adequately documented.

19.6 DOCUMENTATION

Good laboratory practice in the collection and handling of raw data is asimportant in the development phases of biopharmaceutical products as in



5/7

the later stages of manufacture. In order to conform to GLP, a programme ofwork in the laboratory should proceed according to a written study plan. Thestudy plan should define the objectives, rationale and methods of the study

to be performed. In addition, the study plan should designate the individualprincipally responsible for the study (the study director). For research anddevelopment studies, where procedures may require change dependent onresults, the study plan should be structured in such a manner as to retainflexibility.

Procedures, where possible, should follow written study protocols. Suchprotocols should record data such as start and finish times of assays, thematerials and equipment used, the procedures followed and the resultsobtained. This will be justified where certain assays or procedures are per-

formed repeatedly throughout the study. Procedures which are performedonce only, infrequently or variably are more appropriately described and theraw data recorded in laboratory notebooks. Such notebooks should be issuedfor specific studies with the names and signatures of the investigators andstudy director.

The functions of the laboratory should be regulated by SOPs, writtenprocedures for policy relating to all aspects of work, which should be ad-hered to by relevant personnel. SOPs should detail the procedures for allaspects of the working environment, including material receipt and storage,

disinfection procedures, equipment use, calibration, monitoring and mainte-nance, appointment of study directors, documentation control, scheduling ofwork, and report writing and archiving.

19.7 THE ROLE OF THE STUDY DIRECTOR

The role of the study director is critical to the conduct of routine or develop-mental studies to GLP (Department of Health, 1992). As noted above, thestudy director is the individual designated by management who has respon-

sibility for the planning, implementation and reporting of studies. It is theresponsibility of the study director to oversee the elements of the work withthe plan and to ensure the accuracy and validity of the studies performedalone or by others. It is also the responsibility of the study director to preparea final report which accurately reflects the raw data generated during thestudy. The principal duties of the study director are:

to ensure that adequate resources, documentation in the form of SOPs,where suitable, and suitably trained personnel are available to perform the

study prior to commencement. to approve the protocol by dated signature. to ensure appropriate liaison with and awareness of the protocol in all key

staff involved (including quality assurance) in the study.



6/7

to be responsible overall for the technical performance of the study. Thiswill involve continuing review of the study procedures.

to ensure that procedures are being followed accurately. The study director

should be aware of the progress of the study by maintaining effectivecommunication with scientific, administrative and quality assurance per-sonnel.

to ensure that the raw data generated are fully and accurately documentedand that deviations or amendments to the protocol are accurately reflected.

to produce a detailed scientific report which accurately reflects the rawdata obtained in the study.

After audit by quality assurance the study director should sign and date a

statement to the effect that the study was performed according to the prin-ciples of GLP.

19.8 THE ROLE OF QUALITY ASSURANCE

In order to implement an effective quality assurance programme, the qualityassurance unit must be independent of the personnel who perform researchand development studies. In certain facilities it may not be practicable to

maintain personnel dedicated solely to quality assurance. In such cases, oneindividual may be appointed to have permanent, but part-time, responsibil-ity for the quality assurance function. In general, the functions of qualityassurance in relation to research and development are identical to those fornon-clinical safety studies. The principal responsibilities of quality assuranceare:

to maintain a master schedule listing of all studies planned, current orcompleted.

to review study plans before commencement of studies in order to ensurethe completeness and compliance of the protocol with GLP principles, andto identify appropriate phases of the study for monitoring.

to regularly monitor facility operations, periodically review studies anddocuments, schedule and keep appropriate records of audits and inspec-tions of all studies, and report the findings of such reviews and inspectionsto management.

to review facility SOPs before issue in order to ensure clarity, control theproduction and issue of SOPs, and ensure that SOPs are periodically

reviewed by appropriate personnel. to audit raw data either during inspections or by audit of final reports.



7/7

19.9 SUMMARY

Although the GLP regulations pertain specifically to non-clinical laboratory

safety studies, they can be readily applied to experimental research anddevelopment. The implementation of such standards in the research anddevelopment of biological agents for gene therapy would enhance consider-ably the existing measures employed to ensure product safety.

REFERENCES

1 Department of Health (1989).Good Laboratory Practice: The United Kingdom Compli-

ance Programme.Department of Health, London.2 Department of Health (1992). Good Laboratory Practice and the Role of the StudyDirector (Good Laboratory Practice United Kingdom Compliance Programme). Depart-ment of Health, London.

3 Department of Health (1997). The Good Laboratory Practice Regulations 1997.Depart-ment of Health, London.

4 Food and Drug Administration (1997). Good Laboratory Practice for Non-ClinicalLaboratory Studies. Department of Health and Human Services, Code of FederalRegulations 21, part 58, pp. 272285.

5 McLean CM, Docherty D, Shepherd AJ (1997). Key raw materials used in themanufacturers of biotechnology derived products. Eur. J. Parenteral Sci. Biotechnol-

ogy Special Issue, May, 2730.6 Medicines Control Agency (1993). Rules and Guidance for Pharmaceutical Manufac-turers. Her Majestys Stationery Office, London.

7 Smith KT, Shepherd AJ, Boyd JE, Lees GM (1996). Gene delivery systems for use ingene therapy: an overview of quality assurance and safety issues. Gene Therapy 3:190200.


good laboratory practice in the research and development lab

Documents