Regulations, Quality Systems and Documentation

Adapted from

Basic Laboratory Methods for Biotechnology

by

Lisa Seidman and Cynthia Moore

Quality Systems

• Laboratories are concerned with quality• Biotechnology industries are concerned with

product quality• Clinical labs are concerned with quality of test

results and instrument performance• Research labs are concerned with quality of

knowledge• Quality systems consist of organizational

structure, responsibilities, procedures, processes, and resources that together ensure the quality of a product or service

Quality in Research Labs

• Thought of as “doing good science”

• Consistent, thoughtful, and effective methods

• Keeping honest and thorough records

• Verifying all results and employing “good laboratory practices”

• Scientists submit results of work to journals to be subjected to peer review

Quality in Regulated Companies

• Quality is strictly enforced in industry• cGMPs (current Good Manufacturing Practices)

are used in drug and related medical product producing companies– Covers everyone from makers of medical products to

people who distribute, package, sell or use the items– GMPs are formalized into regulations and codified in

the CFR– Intended to manage all areas of product quality and

safety, from pre-production to post-production testing

Quality in Regulated Companies

• GLPs (Good Laboratory Practices) governing labs involved in nonclinical studies– EPA uses GLPs governing agrochemical product testing

• CLIA ’88 (The Clinical Laboratory Improvement Amendments of 1988) is a system of regulations intended to ensure quality of results generated by labs performing tests on human specimens

Regulations

• Objective and focus on safety, efficacy, honesty

• Don’t cover subjective areas of quality

• Imposed and enforced by the government acting on behalf of the consumer

• Industries are required to comply

Quality With Voluntary Standards

• Biotech companies making products not regulated by government may choose to comply with voluntary quality standards– Standard is a concept, method, or way of doing

things that is established by some authority, by custom, or by general agreement

• Established by various organizations, agencies, and other entities

• Only voluntary compliance is expected, not enforced as laws

Quality Standards

• ISO (International Organization for Standardization) 9000 is a series of quality standards– Many companies follow ISO 9000 standards to improve product

quality, make processes cost-effective, increase profitability, demonstrate quality manufacturing to potential customers

– Companies develop and follow their own quality plan with ISO 9000

• Formalized and documented in quality manual• Hires certified auditor to evaluate their status• If they are in compliance and all parts of quality program exist, they

will be ISO certified– ISO Guide 25 focuses on lab specific issues, similar to ISO 9000

Quality Documents

• All quality systems share a foundation of documentation

• GMP regulations and ISO documents are written in very general terms– FDA interprets and enforces GMP requirements in

guidance documents called “Guidelines” and “Points to Consider”

Documentation

• The FDA says “if it isn’t written down, it isn’t done”– Any documentation that is missing will prohibit the sale of

that batch of product– Documents associated with products must be completed,

stored securely, and protected

• Research must be appropriately documented to be credible

• Documentation protects personnel in the event of future questions regarding procedure, quality, safety, equipment functionality regardless of facility

Functions of Documentation• To record what the individual has done and observed• To establish ownership for patent purposes• To tell workers how to perform particular tasks• To establish specifications by which to evaluate a process or

product• To demonstrate that a procedure was performed correctly• To record operating parameters of a lab instrument or

manufacturing vessel• To demonstrate an evidence “trail” verifying that a product meets

its requirements• To ensure traceability: the ability to trace the history,

applications, and location of a product and to trace the components of a product

• To establish a contract between a company and consumers• To establish a contract between a company and regulatory

agencies

Types of Documents

• Documentation types and systems vary depending on the workplace

• The regulatory agency or agencies dictates the types of documentation required for each particular industry

• Voluntary compliance with standards may dictate additional documenation

Types of Documentation

• Lab notebooks• SOPs• Forms • Protocols• Reports• Equipment/Instrument

logbooks• Instrument

printouts/recordings

• Electronic documents• Analytical lab

documents• Numbering systems• Labels• Chain of custody• Training reports

Management of Change

• Changes must be reviewed, evaluated, and approved before and after they are made– Require detailed assessment and evaluation

• Some changes must be approved by proper regulatory agency for regulated companies

• Change must be controlled and done in a procedural manner

• The QA/QC and R&D sections must be involved in change in most instances

Production Facility Specific Documents

• Batch records are collections of documents associated with a particular batch of a product

• Regulatory submissions are forms filled out and sent to regulatory agencies to inform them of what a company is planning and /or to ask permission to test or sell a product

• Release of final product record is filled out when a product has been approved for sale

SOPs

• Standard Operating Procedures– Detail how to complete a task; what all is involved

• Preliminary work must be done before writing an SOP, like listing important characteristics of final product

• What considerations contribute to quality should be evaluated and described

• Guidelines are established by many federal agencies: FDA, EPA, etc.

SOP Guidelines

• SOP must be reviewed and accepted before use• The writer has to sign it and accept responsibility for it• A second individual knowledgeable about the work also

approves and signs• In companies a QA employee also signs it• SOPs may require changes• Old SOPs must be destroyed or made unavailable when

changes are made except for historical copies• Changes may need to go through several levels for

acceptance• Each revision needs a date and revision number

SOP Components• Title• Author• Statement of purpose• ID number and date• Revision number, date of revision• Statement of scope describing when procedure is relevant• Who is qualified to follow the procedure, statement of responsibility• Materials required, including manufacturers and identifying information• Calculations required, may need an example• Steps in the process• References to other documents, as required• How to document performance and references to forms

Potential SOP Problems

• SOP says what to do, not how to do it

• Procedure written by someone inexperienced

• SOP is too detailed or not detailed enough

• Procedure not written in correct order

• SOP not updated as needed

• Right SOP can’t be found or older version is used

Forms

• Often used in conjunction with SOP and filled in as procedure is followed

• Blanks must be filled in as employee goes along, requiring them to monitor their process

• Serves as a reminder to record necessary information

• Some key steps may need to be signed

Protocols

• Some industries used the term to describe a procedure that tells an operator how to perform a task or an experiment that is intended to answer a question or test a hypothesis

• May also be used to describe a procedure that may only be used one time

• Protocols typically lead to an answer, SOPs give procedural directions

Reports

• Document that describes the results of an executed protocol

• What was done, by whom, why, data obtained, conclusions drawn

• Written in narrative format• Scientific research published in journals• Private company investigation reports may

not be published but are required to be available for inspection

Logbooks and Instrument Recordings

• Logbooks are chronological records about status and maintenance of equipment or instruments

• Instruments may generate automatic result printouts– Considered to be raw data– May be affixed to notebooks or filed– Some instruments continuously monitor themselves

and record parameters as they operate– Must be thoroughly identified and be signed and

dated by technician

Electronic Documentation

• Used to control and monitor instruments

• Recording and analysis of data

• Storage of protocols and SOPs

• Printouts, disks, other media may be generated by computers

• Appropriate security and validity of electronic documentation must be established for it to be of value

Analytical Lab Documents

• Analytical labs measure properties of a sample

• Environmental labs, clinical labs, reference labs

• Documentation must be provided concerning methodology used and sample identification

Identification Numbers and Labels

• ID numbers used to uniquely identify items

• Raw materials, documents, equipment, parts, product batches, chemicals, solutions, lab samples

• Tells what it is and which one in the set it is

• Labels identify equipment, materials, products, other items

• Have various types of information

Label Components

• Preparation date• Person responsible• ID number• Lot number• Identity, composition, or name of the item• Safety information• Name of company or institution• Storage and stability information

Chain of Custody

• Provides a paper trail for samples• Used to organize information about samples• Each sample has a unique ID number• Records show sample source, collector,

transporter, condition upon receipt, date of receipt, sample processing and testing methods and personnel, storage information, disposition

• Every move along the process must be logged

Training Reports

• Keep track of individuals who have been trained in a facility

• Show what training has been completed

• Dates of training

• Purpose of training

• Demonstrates who is competent to perform what job

Production Facility Specific Documents

• Batch records– Accompany a particular batch or product,

directing the process by which a product is to be made, raw materials required, SOPs to follow

– Stays with product as it is made– Includes blanks to be filled in as procedures

are performed– Must be complete, readable, correct

Batch Record Components

• Product identification• Document identification• Company name• Dates of manufacturing• Step by step account of processing and testing

to be done• Monitoring specifications• Raw data to be collected and blanks to record it

in• Materials and equipment to be used• Required signatures

Regulatory Submissions & Release of Final Product Records

• Regulatory submissions are completed to meet the requirements of an outside regulatory agency– Ask for permission, report activity

• Release documents are completed to show when a product has been manufactured and tested– Certifies the product, shows specifications,

established the documentation has been reviewed and approved, state the product is ready to be sold