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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Computerized Systems in Drug Establishments (2/83)

 

FEBRUARY, 1983

National Center for Drugs and Biologics
and
Executive Director of Regional Operations

 

REFERENCE MATERIALS AND TRAINING AIDS FOR INVESTIGATORS

 

U.S. DEPT. OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION

 

Division of Drug Quality Compliance (HFN-320)
Associate Director for Compliance
Office of Drugs
National Center for Drugs and Biologics

 

and

 

Division of Field Investigations (HFO-500)
Associate Director for Field Support
Executive Director of Regional Operations

 

I.   INTRODUCTION

 

Computers are being used in increasing numbers in the      

pharmaceutical industry.  As microprocessors become more    

powerful, reliable, and less expensive we can expect the    

proliferation of this technology, with increasing use by    

even very small pharmaceutical establishments.  Computer    

systems are used in a wide variety of ways in a    

pharmaceutical establishment, such as, maintenance of    

quarantine systems for drug components, control of    

significant steps in manufacturing the dosage form, control 

of laboratory functions, management of warehousing and      

distribution activities.  Computer systems may control one  

or more of these phases, either singly or as part of a    

highly automated integrated complex.

The purpose of this guide is to provide the field

investigator with a framework upon which to build an

inspection of drug establishments which utilize computer

systems.  This document is not intended to spell out how to

conduct a CGMP drug inspection or set forth reporting

requirements, but rather what aspects of computerized

systems to address during such inspections and suggestions

on how to address the systems.

     

This guide discusses some potential problem areas in

application of computer systems, provides inspectional

guidance, and includes a glossary of terms the investigator

should be aware of prior to performing the inspection.

Questions and suggestions concerning this guide should be

directed to the Manufacturing Standards and Industry Liaison

Branch, Division of Drug Quality Compliance (HFN-323),

443-5307; or the Investigations and Engineering Branch,

Division of Field Investigations (HFO-520), 443-3276.

 

II.  OVERVIEW

 

When a computer system is first encountered in a drug

establishment, it may be useful for inspectional purposes to

begin with a broad overview of the system(s).  Determine

exactly what processes and functions are under computer

control or monitoring and which are not.  Computer

involvement may be much more limited than it may initially

appear.  For example, computer application may be limited to

control of a sterilization cycle in a single autoclave, or

maintenance of distribution records.

For each drug process under computer control determine the  

general system loop (sensors, central processor, activator).

For example, the general system loop for a steam autoclave

under computer control could consist of temperature/pressure

sensors connected to a microprocessor which transmits

commands to steam/vacuum control valves.

The overview should enable the investigator to identify

those computer controlled processes which are most critical 

to drug product quality.  These are the systems which, of

course, merit closer inspection.

 

III. HARDWARE

 

For each significant computerized system, it may be helpful

to prepare or oed schematic drawing of the

attendant hardware.  The drawing need only include major

input devices, output devices, signal converters, central

processing unit, distribution systems, significant

peripheral devices and how they are linked.  Figure 1 is an

example of such a drawing.

 

figure 1. example of computer system schematic

 

 

Hardware Suppliers.  During the inspection identify the

manufacturers/suppliers of important computer hardware,

including the make and model designations where possible.

Hardware to identify this way includes CPUs, disk/tape

devices, CRTs, printers, and signal converters.  Proper

identification of hardware will enable further follow-up at

computer vendors should that be needed.

 

     A.   Types

             1.   Input Devices.  Equipment which translates

external information into electrical pulses which

the computer can understand.  Examples are

thermocouples, flow meters, load cells, pH meters,

pressure gauges, control panels, and operator

keyboards.  Examples of functions are:

               a)   Thermocouple provides temperature input for

  calculation of F value in a sterilizer.

               b)   Flow meter provides volume of liquid

  component going into a mixing tank.

               c)   Operator keyboard used to enter autoclave    

  load pattern number.

             2.   Output Devices.  Equipment which receives

electrical pulses from the computer and either

causes an action to occur, generally in

controlling the manufacturing process, or

passively records data.  Examples are valves,

switches, motors, solenoids, cathode ray tubes

(CRTs), printers, and alarms.  Examples of

functions are:

               a)   Solenoid activates the impeller of a mixer.

               b)   Valve controls the amount of steam delivered

  to a sterilizer.

               c)   Printer records significant events during

 sterilization process.

               d)   Alarm (buzzer, bell, light, etc.) sounds when

  temperature in a holding tank drops below

  desired temperature.

             Most active output devices will be in proximity to

the drug processing equipment under control, but

not necessarily close to the CPU.  Passive output

devices, however, may well be remote from the

process or the CPU.

             3.   Signal Converters.  Many input and output devices

operate by issuing/receiving electrical signals

which are in analog form.  These analog signals

must be converted to digital signals for use by

the computer; conversely, digital signals from the

computer must be converted into analog signals for

use by analog devices.  To accomplish this, signal

converter devices are used.

             4.   Central Processing Unit (CPU).  This is the

controller containing the logic circuitry of a

computer system which conducts electronic

switching.  Logic circuits consist of three basic

sections - memory, arithmetic, and control.  The

CPU receives electrical pulses from input devices

and can send electrical pulses to output devices.

It operates from input or memory instructions.

Examples and functions are:

               a)   Programmable controllers can be used for

relays, timers and counters.

               b)   Microprocessors can be used for controlling a

steam valve, maintaining pH, etc.  They

consist of a single integrated circuit on a

chip.  This is the logic circuit of a

microcomputer and microprocessors are often

the same as a microcomputer.

               c)   Microcomputers and minicomputers can be used

to control a sterilization cycle, keep

records, run test programs, perform lab data

analysis, etc.

               d)   Mainframe computers are usually used to

coordinate an entire plant, such as

environment, production, records, and

inventory.

                   The distinction between CPUs is becoming less

apparent with miniaturization of parts, CPUs are

generally ranked by size from "large" mainframes

to desk top microcomputers.

             5.   Distribution System.  The interconnection of two

or more computers.  Also known as distributed

processing.  Generally, each computer is capable

of independent operation but is connected to other

computers in order to have a back-up system, to

receive operating orders and to relay what is

executed by other computers.  Typical of such

distribution systems is the linkage of smaller or

less powerful units to larger or more powerful

units.  For example, a minicomputer may command

and communicate with several microcomputers.  A

large CPU may also act as a "host" for one or more

other CPU's.  When such systems are encountered

during an inspection, it is important to know the

configuration of the system and exactly what

commands and information can be relayed amongst

the computers.  Figure 2 contains examples of

distributed control.

 

 

figure 2. example of distributed computer control configurations

 

Networks are generally extensions of distributed

processing.  They typically consist of connections

between complete computer systems which are

geographically distant.  Potentially,

pharmaceutical companies could have international

networks by using modems and satellites.

              6.   Peripheral Devices.  All computer associated

devices external to the CPU can be considered

peripheral devices.  This includes the previously

discussed input and output devices.  Many

peripheral devices can be both input and output,

they are commonly known as I/O devices.  These

include CRTs, printers, keyboards, disk drives,

modems, and tape drives.

 

     B.   Key Points

              1.   Location.  Three potential problems have been

identified with location of CPUs and peripheral

devices.  These are:

             a)   Hostile Environments.  Environmental extremes

of  temperature, humidity, static, dust,

power feed line voltage fluctuations, and

electromagnetic interference should be

avoided.  Such conditions may be common in

certain pharmaceutical operations and the

investigator should be alert to locating

sensitive hardware in such areas.

Environmental safeguards maybe necessary to

ensure proper operation.  There are numerous

items on the market (such as line voltage

monitors/controllers and anti-static floor

mats) designated to obviate such problems.

Physical security is also a consideration in

protecting computer hardware from damage; for

example, books and bottles of reagents should

not be stored on top of microprocessors.

Likewise eating, drinking and smoking should

be restricted in rooms housing mainframes.

             b)   Excessive Distances between CPU and

Peripheral Devices.  Excessively long low

voltage electrical lines from input devices

to the CPU are vulnerable to electromagnetic

interference.  This may result in inaccurate

or distorted input data to the computer.

Therefore, peripheral devices

located as near to the CPU as practical and

the lines should be shielded from such

sources of electromagnetic interference as

electrical power lines, motors, and

fluorescent lighting fixtures.  In a

particularly "noisy" electronic environment

this problem might be solved by the use of

fiber optic lines to convey digital signals.

 c)   Proximity of Input Devices to Drug

Processing.  Input devices which are remote

from (out of visual range of) the drug

processing equipment are sometimes met with

poor employee acceptance.

             2.   Signal Conversion.  Proper analog/digital signal

conversion is important if the computer system is

to function accurately.  Poor signal conversion

can cause interface problems.  For example, an

input sensor may be feeding an accurate analog

reading to a signal converter, but a faulty signal

converter may be sending the CPU an inappropriate

digital signal.

                    3.   I/O Device Operation.  The accuracy and

performance of these devices are vital to the

proper operation of the computer system.  Improper

inputs from thermocouples, pressure gauges, etc.,

can compromise the most sophisticated

microprocessor controlled sterilizer.  These

sensors should be systematically calibrated and

checked for accurate signal outputs.

                    4.   Command Over-rides.  In distributed systems it is

important to know how errors and command

over-rides at one computer are related to

operations at another computer in the system.  For

example, if each of three interconnected

microcomputers runs one of the three sterilizers,

can a command entered at one unit inadvertently

alter the sterilization cycle of a sterilizer

under the control of a different microcomputer on

the line?  Can output data from one unit be

incorrectly processed by another unit?  The limits

on information and command for

distributed system  should be clearly established

by the firm.

              5.   Maintenance.  Computer systems usually require a

minimum of complex maintenance.  Electronic

circuit boards, for example, are usually easily

replaced and cleaning may be limited to dust

removal.  Diagnostic software is usually available

from the vendor to check computer performance and

isolate defective integrated circuits.

Maintenance  procedures should be stated in the

firm's standard operating procedures.  The

availability of spare parts and access to

qualified service personnel are important to the

operation of the maintenance program.

 

     C.   Validation of Hardware

The suitability of computer hardware for the tasks

assigned to pharmaceutical production must be

demonstrated through appropriate tests and challenges.

The depth and scope of hardware validation will depend

upon the complexity of the system and its potential

affect on drug quality.

     The validation program need not be elaborate but should

be sufficient to support a high degree of confidence

that the system will consistently do what it is

supposed to do.  In considering hardware validation the

following points should be addressed:

       1.   Does the capacity of the hardware match its

assigned function?  For example, in a firm using a

computer system to maintain its labeling text,

including foreign language labeling, do the CRT

and printer have the capacity to write foreign

language accent marks?

       2.   Have operational limits been identified and

considered in establishing production procedures?

For example, a computer's memory and connector

input ports may limit the number of thermocouples

a computer can monitor.  These limits should be

identified in the firm's standard operating

procedures.

       3.   Have test conditions simulated "worst case"

production conditions?  A computer may function

well under minimal production stress (as in

vendor's controlled environment) but falter under

high stresses of equipment speed, data input

overload or frequent or continuous multi-shift use

(and a harsh environment).  Therefore, it is

insufficient to test computer hardware for proper

operation during a one hour interval, when the

system will be called upon in worst case

conditions to run continuously for 14 days at a

time.  Some firms may test the circuits of a

computer by "feeding" it electrical signals from a

signal simulator.  The simulator sends out

voltages which are designed to correspond to

voltages normally transmitted by input devices.

When simulators are connected to the computer, the

program should be executed as if the emulated

input devices were actually connected.  These

signal simulators can be useful tools for

validation; however, they may not pose worse case

conditions and their accuracy in mimicking input

device performance should be established.  In

addition, validation runs should be accomplished

on line using actual input devices.  Signal

simulators can also be used to train employees on

computer operations without actually using

production equipment.

       4.   Have hardware tests been repeated enough times to

assure a reasonable measure of reproducibility and

consistency?  In general, at least three test runs

should be made to cover different operating

conditions.  If test results are widely divergent

they may indicate an out of control state.

       5.   Has the validation program been thoroughly

documented?  Documentation should include a

validation protocol and test results which are

specific and meaningful in relation to the

attribute being tested.  For example, if a

printer's reliability is being tested it would be

insuess the results merely as

"passes," in the absence of other qualifying data

such as printing speeds, duration of printing, and

the number of input feeds to the printing devices.

       6.   Are systems in place to initiate revalidation when

significant changes are made?  Revalidation is

indicated, for example, when a major piece of

equipment such a circuit board or an entire CPU is

replaced.  In some instances identical hardware

replacements may adequately be tested by the use

of diagnostic programs available from the vendor.

In other cases, as when different models of

hardware are introduced, more extensive testing

under worst case production conditions, is

indicated.

             Much of the hardware validation may be performed

by the computer vendor.  However, the ultimate

responsibility for suitability of equipment used

in drug processing rests with the pharmaceutical

manufacturer.  Hardware validation data and

protocols should be kept at the drug

manufacturer's facility.  When validation

information is produced by an outside firm, such

as the computer vendor, the records maintained by

the drug establishment need not be all inclusive

of voluminous test data; however, such records

should be reasonably complete (including general

results and protocols) to allow the drug

manufacturer to assess the adequacy of the

validation.  A mere certification of suitability

from the vendor, for example, is inadequate.

 

 IV.  SOFTWARE

 

      Software is the term used to describe the total set of

programs used by a computer.  These programs exist at

different language levels, generally the higher the level,

the closer the text is to human language.  These levels are

set forth below.  During the inspection identify key

computer programs used by the firm.  Of particular

importance are those programs which control and document

dosage form production and laboratory testing.  Usually a

firm can readily list the names of such programs on a CRT

display or in hard copy.  Such a list is sometimes called a

menu or main menu.

 

       A.   Levels

             1.   Machine Language.  This laof coded

instructions, represented by binary numbers, which

are executed directly by the computer.

             2.   Assembly Language.  Instructions are represented

by alphanumeric abbreviations.  These programs

must be converted into machine language, sometimes

called "object programs," before they can be

executed.  Programs which translate assembly

programs to object programs are called assemblers.

Different computers have different assembly

languages.  Computer manufacturers usually provide

the assembler program.

             3.   High Level Language.  This language is

characterized by a vocabulary of English words and

mathematical symbols.  These are source programs

which must be translated by a compiler or

interpreter into an object program.  High level

languages generally operate the same on any

computer which accepts the language although there

may be different versions of the same language.

Examples are FORTRAN, BASIC, and COBOL.

             4.   Application Language.  This is generally based on

a high level language but modified for a specific

industry application and uses the vocabulary of

that industry.  Examples are AUTRAN (Control Data

Corporation) and Foxboro Process Basic.

 

       B.   Software Identification

For the key computer programs used by a firm, the

following items should be identified:

             1.   Language.  High level or application name should

be determined (or machine or assembly language).

             2.   Name.  Programs are usually named with some

relationship to what they do, i.e. Production

Initiation, Batch History Transfer or Alarms.

             3.   Function.  Determine what the purpose of the

program is, i.e., start production, record and

print alarms, or calculate F.

             4.   Input.  Determine inputs, such as thermocouple

signals, timer, or analytical test results.

             5.   Output.  Determine what outputs the program

generates.  These may be a form of mechanical

action (valve actuation) or recorded data

(generation of batch records).

             6.   Fixed Setpoint.  This is the desired value of a

process variable which cannot be changed by the

operator during execution.  Determine major fixed

setpoints, such as desired time/temperature curve,

desired pH, etc.  Time may also be used as a set

point to stop the process to allow the operator to

interact with the processing.

             7.   Variable Set point.  This is the desired value of

a process variable which may change from run to

run and must usually be entered by the operator.

For example, entering one of several sterilizer

load patterns into a sterilization computer

process.

             8.   Edits.  A program may be written in such a manner

as to reject or alter certain input or output

information which does not conform to some

pre-determined criterion or otherwise fall within

certain pre-established limits.  This is an edit

and it can be a useful way of minimizing errors;

for example, if a certain piece of input data must

consist of a four character number, program edits

can be used to reject erroneous entry of a five

character number or four characters comprised of

both numbers and letters.  On the other hand,

edits can also be used to falsify information and

give the erroneous impression that a process is

under control; for example, a program output edit

may add a spurious "correction" factor to F values

which fall outside of the pre-established limits,

thus turning an unacceptable value into an

ue.  It is, therefore, important

to attempt to identify such significant program

edits during the inspection, whenever possible.

Sometimes such edits can manifest themselves in

unusually consistent input/output information.

             9.   Input manipulation.  Determine how a program is

set up to handle input data.  For example,

determine what equations are used as the basis for

calculations in a program. When a process is under

computer control determine, in simplified form

such as a flow chart, how input is handled to

accomplish the various steps in the process.  This

does not mean that a copy of the computer program

itself needs to be reviewed.  However, before

computerized control can be applied to a

pharmaceutical process there usually needs to be

some source document,  written in English, setting

forth in logical steps what needs to be done; it

would be useful to review such a document in

evaluating the adequacy of conversion from manual

to computerized processing.

            10.  Program Over-rides.  A program may be such that

the sequence of program events or program edits

can be over-ridden by the operator.  For example,

a process controlling program may cause a mixer to

stop when the mixer's contents reach a

predetermined temperature.  The program may

prevent the mixer from resuming activity until the

temperature has dropped back to the established

point.  However, the same program may allow an

operator to over-ride the stop and reactivate the

mixer even at a temperature which exceeds the

program limit.  It is therefore important to know

what over-rides are allowed, and if they conflict

with the firm's SOP.

 

       C.   Key Points

             1.   Software Development.  During the inspection

determine if the computer programs used by the

firm have been purchased as "canned" from outside

vendors, developed within the firm, prepared on a

customized basis by a software producer, or some

combination of these sourams are

highly specialized and may be licensed to

pharmaceutical establishments.  If the programs

used by the firm are purchased or developed by

outside vendors determine which firms prepared the

programs.

                   In some cases "canned" or customized programs may

contain segments (such as complex algorithms)

which are proprietary to their authors and which

cannot normally be readily retrieved in program

code without executing complex code breaking

schemes.  In these cases the buyer must accept on

faith that the software will perform properly.  If

the drug manufacturer is using such a program to

control or monitor a significant process,

determine what steps the firm has taken to assure

itself that such program blind spots do not

compromise the program performance.

                   Where drug firms develop their own application

programs, review the firm's documentation of the

approval process.  This approval process should be

addressed in the firm's SOP.  It may be useful to

review the firm's source (English) documents which

formed the basis of the programs.

             2.   Software Security.  Determine how the firm

prevents unauthorized program changes and how data

are secure from alteration, inadvertent erasures,

or loss (21 CFR 211.68).  Some computers can only

be operated in a programming mode when two keys

are used to unlock an appropriate device.  When

this security method is used, determine how use of

keys is restricted.  Another way of achieving

program security is the use of ROM (read only

memory), PROM (programmable read only memory), or

EPROM (erasable programmable read only memory)

modules within the computer to "permanently" store

programs.  Usually, specialized equipment separate

from the computer is needed to change an EPROM or

establish a program in PROM so that changes would

not be made by the operator.  A program in EPROM

is erase the module (which has a

quartz window) to ultraviolet light.  In these

cases a program is secure to the extent it can't

be over-ridden by the operator.  Determine who in

the firm has the ability and/or is authorized to

write, alter or have access to programs. The

firm's security procedures should be in writing.

Security should also extend to devices used to

store programs, such as tapes, disks and magnetic

strip cards.  Determine if accountability is

maintained for these devices and if access to them

is limited.  For instance, magnetic strip cards

containing a program to run a sterilization cycle

may be kept in a locked cabinet and issued to

operators on a charge-out basis with return of the

card immediately after it is used.

 

       D.   Validation of Software

             It is vital that a firm have assurance that computer

programs, especially those that control manufacturing

processing, will consistently perform as they are

supposed to within pre-established operational limits.

Determine who conducted software validation and how key

programs were tested.  In considering software

validation the following points should be addressed:

             1.   Does the program match the assigned operational

function?  For example, if a program is assigned

to generate batch records then it should account

for the maximum number of different lots of each

component that might be used in the formulation.

Consider what might happen when three lots of a

component are used with a program designed to

record lot designations and quantities for up to

two different lots of each component.  The first

lot may be accurately recorded, but the next two

lots might be recorded as a single quantity having

the second lot designation; the resultant computer

generated record therefore would fail to show the

use of three different lots and the quantities of

each of the second and third lots going into the

mixture.

             2.   Have test conditions simulated "worst case"

production limits?  A program should be tested,

for example, under the most challenging conditions

of process speed, data volume and frequency.  Date

should be considered in this aspect of

validation.  For example, the number of characters

allowed for a lot number should be large enough to

accommodate the longest lot number system that

will be used.

             3.   Have tests been repeated enough times to assure

consistent reliable results?  Divergent results

from replicate data entries may signify a program

bug.  In general, at least three separate runs

should be made.

             4.   Has the software validation been thoroughly

documented?  Documentation should include a

testing protocol and test results which are

meaningful and specific to the attribute being

tested; individuals who reviewed and approved the

validation should be identified in the

documentation.

             5.   Are systems in place to initiate revalidation when

program changes are made?  If process parameters

such as time/temperature, sequence of program

steps, or data editing/handling are changed then

revalidation is indicated.

             Although much of the software validation may be

accomplished by outside firms, such as computer or

software vendors, the ultimate responsibility for

program suitability rests with the pharmaceutical

manufacturer.  Records of software validation should be

maintained by the drug establishment, although when

conducted by outside experts such records need not be

voluminous but rather complete enough (including

protocols and general results) to allow the drug

manufacturer to assess the adequacy of the validation.

Mere vendor certification of software suitability is

inadequate.  Signal simulators many be used in software

validation.  These are discussed in point No. 3 of

Validation of Hardware.

 

V.   COMPUTERIZED OPERATIONS

       A.   Networks

             If the firm is on a computer network it is important to

know:  (1) what output, such as batch production

records, is sent to other parts of the network; (2)

what kinds of input (instructions, programs) are

received; (3) the identity and location fo establishments

which interact with the firm; (4)the

extent and nature of monitoring and controlling

activities exercised by remote on-net establishments;

and (5) what security measures are used to prevent

unauthorized entry into the network and possible drug

process sabotage.

          It is possible under a computer network for

manufacturing operations conducted in one part of the

country to be documented in batch records on a

real-time basis in some other part of the country.

Such records must be immediately retrievable from the

computer network at the establishment where the

activity took place (21 CFR 211.180).

       B.   Manual Back-up Systems

             Functions controlled by computer systems can generally

also be controlled by parallel manual back-up systems.

During the inspection determine what functions can be

manually controlled and identify manual back-up

devices.  Process controls are particularly important.

Determine the interaction of manual and computerized

process controls and the degree to which manual

intervention can over-ride or defeat the computerized

process.  The firm's SOP should describe what manual

over-rides are allowed, who may execute them, how and

under what circumstances.  Determine if and how manual

interventions are documented; a separate log may be

kept of such interventions.  The computer system may be

such that it detects, reacts to and automatically

records manual interventions and this should be

addressed during the inspection.

       C.   Input/Output Checks

             Section 211.68 of the CGMP regulations requires that

input to and output from the computer system be checked

for accuracy.  While this does not mean that every bit

of input and output need be checked it does mean that

checking must be sufficient to provide a high degree of

assurance that input and output are, in fact, accurate.

In this regard theome reasonable

judgment as to the extent and frequency of checking

based upon a variety of factors such as the complexity

of the computer systems.  The right kinds of input

edits, for example, could mitigate the need for

extensive checks.

             During the inspection determine the degree and nature

of input/output checks and the use of edits and other

built-in audits.

             Input/output error handling has been a problem in

computer systems.  Determine the firm's error handling

procedures including documentation, error verification,

correction verification, and allowed error over-rides

including documentation of over-rides.

             As an illustration of inadequate input/output checks

and error handling consider the situation of a firm

which uses a computer system to maintain and revise

labeling text.  Master labeling is recorded on a disk

and when a change is to be made the operator calls up a

copy of the text from the master disk onto a CRT.  The

copy is then revised at the CRT, printed on paper and

electronically printed onto another disk for storage

until the paper copy is proofread and approved; once

the paper copy is approved, the text on the temporary

storage disk is transferred to the master disk

replacing the previous text.  As an example, the

operator calls up a label to change the directions for

use section, correctly makes the change but

accidentally erases the quantity of content statement

that read 100 ml.  The operator "corrects" this error

by re-entering what was believed to be the correct

statement but what, in fact, was "150 ml."  The

proof-readers do not detect this error because their

standard operating procedure is to proof only those

portions of the labeling-in this case directions for

use-which were supposed to be changed (a case of

inadequate output check).  In addition, the operator

does not document the error or the "correction" and the

"correction" is not verified.  This would probably

result product. Section 211.68 of the

CGMP regulations also requires maintenance of accurate

back-up files of input data which are secure from

alteration, loss or inadvertent erasure.  These back-up

files need not be on paper, however.  They may, for

instance, consist of duplicate tapes, disks or

microfilm.  During the inspection determine if the firm

has such a back-up system, the form of such a system,

and how it is protected.  If a back up file is printed

on thermal paper note if older files have faded.  (It

has been reported that the printing on thermal paper

has a tendency to fade with time.)

       D.   Process Documentation

             Most computer systems are capable of generating

accurate and detailed documentation of the drug process

under computer control.  What is important is that

records within the scope of the CGMP regulations, which

happen to be in computerized form, do contain all of

the information required.  For example, if batch

production records are generated by computer determine

if they contain all of the information required to be

in batch records.

 

       E.   Monitoring of Computerized Operations

             Determine the degree to which the firm's personnel

monitor computerized operations.  Is such monitoring

continuous or periodic?  What functions are monitored?

For example, a firm's computer system may be used to

maintain the pH in a reaction vessel, but if the firm

does not sufficiently monitor the system they may fail

to detect a hardware problem which could allow the pH

to be out of tolerance.  During the inspection, where

possible, spot-check computer operations such as:

             1.   Calculations; compare manual calculations of input

data with the automated calculations or ask the

firm to process a given set of input values and

compare automated results against known results.

              2.   Input recording; compare sensor indications with

what the computer indicates, for example.  As

mentioned previously, some analog signals may be

incorrectly converted to digital signals and

built-in programming edits may alter input data.

For example, a thermocouple indicating 80øC may

read out on a CRT as 100øC or any other

temperature if the signal con   malfunctioning.

             3.   Component quarantine control; for example, check

the actual warehouse location of a particular lot

against its location as reported by computer.  If

the computer indicates that a particular lot has

passed a certain number of laboratory tests then

the laboratory records may be checked to confirm

the computer information.

             4.   Timekeeping; where computers are reporting events

and controlling a process in real time, spot-check

the time accuracy against a separate time piece;

accurate timekeeping is especially important where

time is a determinative or limiting factor in a

process such as sterilization.  It should be noted

that some computer systems run on a 12 hour clock

whereas others run on a 24 hour clock.

             5.   Automated cleaning in-place; determine the

procedure used, how the firm assures adequacy of

cleaning, and residue elimination.

             6.   Tailings accountability; where batches are

produced back to back on a continuous basis under

computer control are batch tailings accounted for

in subsequent handling and formulation?  For

example, at the conclusion of a run the computer's

memory may be downloaded and the controlling

program reset.  At an initial step the computer

may call for a programmed quantity of material to

be added to a hopper; the amount to be added can

be based upon the tare weight of an empty hopper.

However, if the hopper is not, in fact, empty but

contains tailings of a prior run the result may be

a hopper with more material than called for in the

batch formulation; thus, there may be errors of

yield reconciliation or batch formulation.  During

the inspection determine what limits if any the

firm places on tailings.

 

        F.  Alarms

             A typical computer system er of

built-in alarms to alert personnel to some

out-of-limits situation or malfunction.  Determine what

functions are linked to alarms.  For example, alarms

may be linked to power supply devices, feedback signals

to confirm execution of commands, and pharmaceutical

process conditions such as empty or overflowing tanks.

Determine the alarm thresholds for critical process

conditions and whether or not such thresholds can be

changed by the operator.  For example, if the

temperature of water in a water for injection system is

linked to an alarm which sounds when the temperature

drops below 80øC, can the operator change the threshold

to 75øC?

             Determine how the firm responds when an alarm is

activated. This should be covered in the firm's

standard operating procedures.

             Determine the types of alarms (lights, buzzers,

whistles, etc.) and how the firm assures their proper

performance.  Are they tested periodically and equipped

with in-line monitoring lights to show they are ready?

             Because an activated alarm may signal a significant out

of control situation it is important that such alarm

activations are documented.  Determine how alarm

soundings are documented-in batch records, in separate

logs or automatic electronic recording, for instance.

Can all alarm conditions be displayed simultaneously or

must they be displayed and responded to consecutively?

If an employee is monitoring a CRT display covering one

phase of the operation will that display alert the

employee to an alarm condition at a different phase?

If so, how?

 

        G.  Shutdown Recovery

             How a computer controlled process is handled in the

event of computer shutdown (e.g. power failure) is

significant and can pose a problem.  Shutdown recovery

procedures are not uniform in the industry.  Some

systems, for example, must be restarted from the

initial step in the process sequence and memory of what

has transpired is lost.  Other systems have safeguards

whereby memory is retained and the process is resumed

at the point Determine the

disposition of the computer's memory content (program

and data) upon computer shutdown.

             Determine the firm's shutdown recovery procedure and

whether or not, in the event of computer failure, the

process is brought into a "safe" condition to protect

the product.  Determine such safeguards and how they

are implemented. Where is the point of restart in the

cycle--at the initial step, a random step or the point

of shutdown?  Look for the inappropriate duplication of

steps in the resumption of the process.

             The time it takes to resume a computerized process or

switch to manual processing can be critical, especially

where failure to maintain process conditions for a set

time (e.g. pH control for antibiotic fermentation)

compromises product integrity.  Therefore, note

recovery time for delay-sensitive processes and

investigate instances where excessive delays compromise

product quality or where established time limits (21

CFR 211.111) are exceeded.

             Many systems have the ability to be run manually in the

event of computer shutdown.  It is important that such

back-up manual systems provide adequate process control

and documentation.  Determine if back-up manual

controls (valves, gates, etc.) are sufficient to

operate the process and if employees are familiar with

their operation.  Records of manual operations may be

less detailed, incomplete, and prone to error, compared

to computerized documentation, especially when they are

seldom exercised.  Therefore, determine how manual

operations are documented and if the information

recorded manually conforms with CGMP requirements.

 

VI.  CGMP GUIDANCE

        A.  Hardware

             In general, the hardware of a computer system is

considered to be equipment within the meaning of the

CGMP regulations. Therefore those sections of the

regulations which address equipment apply to hardware.

For example, the following apply:

             1.   21 CFR 211.63 repment be suitably

located to facilitate operations for the

equipment's intended use.

             2.   21 CFR 211.67 requires a maintenance program for

equipment.

             3.   21 CFR 211.68(a) states that computers may be used

and requires a calibration program.

        B.  Software

             In general, software is regarded as records or standard

operating procedures (instructions) within the meaning

of the CGMP regulations and the corresponding sections

of the CGMP regulations apply, for example:

             1.   Record Controls.  21 CFR 211.68(b) requires

programs to ensure accuracy and security of

computer inputs, outputs, and data.

             2.   Record Access.  21 CFR 211.180(c) states that

records required by the regulations shall be

available as part of an authorized inspection at

the establishment for inspection and are subject

to reproduction.  Computer records retrievable

from a remote location are acceptable.

                   In considering the copying of electronic records

however, the act of copying must be reasonable, as

the word reasonable is used in the FD& C Act to

limit how we may conduct inspections.  In some

cases it may be reasonable to copy a disk or tape

whereas in other cases it might not, particularly

where we would have to physically remove the disk

or tape from the establishment in order to copy

it.  (Consider the analogy of removing an entire

file cabinet so that we can copy five pieces of

paper.)  We believe that, rather than copy an

entire disk or tape ourselves, it is preferable to

have the firm generate hard copies of only those

portions of the disk or tape which we need to

document.

             3.   Record Medium.  21 CFR 211.180(d) states that

retained records may be originals or true copies

and, when necessary, ocopying

equipment shall be available.  This concept

applies to magnetic tape and disks.

             4.   Record Retention.  21 CFR 211.180(a) states record

retention requirements.  They are the same for

electronic media and paper.

             5.   Computer Programs.  FD& C Act.  Section 704(a),

for prescription drug products, would allow

inspectional access to computer programs if such

inspection is performed within the constraint of

being reasonable.

                   There are several factors which must be considered

on a case by case basis in determining what is

reasonable in accessing a firm's computer.  For

example, the effect on drug production is a

factor; specifically, if the process of running a

program disrupts drug production in an adverse

manner then that would be unreasonable.  Another

factor is whether or not our manipulations give us

access to unauthorized information; the data we

may be searching with a program may contain some

information we are not entitled to review such as

financial data.  Consider also that some computer

programs are protected by copyright and carefully

licensed to software users; thus, we would not be

able to copy and use such programs without prior

approval of their owners.

             6.   Record Review.  21 CFR 211.180(e) states that

where appropriate records associated with every

batch shall be reviewed as part of a periodic

review of quality standards.  It is acceptable for

a firm to conduct part of the review by running a

computer program which culls out analytical data

from each batch and conducts trend analysis to

determine the need to change product

specifications, manufacturing methods, or control

prata itself must be meaningful

(i.e., specified and relevant to enable an

evaluation to be performed).  It is not necessary

to review each and every bit of information on the

batch record.  However, the computerized trend

analysis data would constitute only a portion of

the data which must be reviewed.  A review must

also be made of records of complaints, recalls,

returned or salvaged products, and investigations

of unexpected production discrepancies (e.g.,

yield reconciliations) and any failures of batches

to meet their specifications.  This information is

usually separate from conventional batch records

and so would not necessarily be reviewed by the

trend analysis program.

             7.   QC Record Review.  21 CFR 211.192 requires the

quality control unit to review and approve

production and control records prior to batch

release/distribution.  If this record screening

review (to check errors and anomalies) is

computerized and is at least as comprehensive and

accurate as a manual review, then it is acceptable

for the QC unit to review a computer generated

exception report as part of the batch release.

The batch record information required by the

regulation must still be retained.  It is also

important that the accuracy and reliability of the

screening program be demonstrated.  It is unlikely

however, that all production and control records

will be computerized; labeling, packaging, and

analytical records may still be in manual form and

would therefore be manually reviewed.

             8.   Double Check on Computer.  21 CFR 211.101(d)

requires verification by a second person for

components added to a batch.  A single check

automated system is acceptable if it provides at

least the same assurance of freedom from errors as

a double check.  If it does provide the same

assurance then we would gain nothing in applying a

redundant second check which adds nothing to

assuring product quality.  The equivalency of an

automated single check system to a manual

check must be shown, however, and this might not

always be possible.  For example, let's say 5

kilograms of a coarse white granular component

must be added to a mixture.  Two individuals

checking the operation may check for the

component's label accuracy, color and granularity,

weight and finally the actual transfer of the

material; if there were a mix-up prior to that

transfer and a different component, say a white

powder, was staged for addition to the batch it is

probable that the double check screening would

detect the error.  On the other hand, a single

check computer system might accurately check the

component weight and physical transfer but not its

granularity or other sign of identification.  In

this case the automated single check would not be

as good as the manual double check.

             9.   Documentation.  21 CFR 211.188(b) (11) requires

that batch production and control records include

identification of each person who conducts,

supervises or checks each significant step in the

process.  The intent is to assure that each step

was, in fact, performed and that there is some

record to show this, from which the history of the

lot could be traced.  It is quite possible that an

automated system can achieve the same, or higher,

level of assurance in which case it may not be

necessary to have persons document the performance

of each event in a series of unbranched automated

events on the production line.  For example, let

us say an automated/computerized system is

designed to perform steps A through Z.  If the

program is such that every step must be executed

properly before step Z is completed then an

acceptable means of complying with the regulation

would be all of the following:  (1) documentation

of the program; (2) validation that no step can be

missed or poorly executed; and (3) documentation

of the initial and final steps.  It would not be

necessary in this example to document steps B

through Y.

            10.  Reproduction Accuracy.  21 CFR 211.188(a) requires

the batch record to contain a

reproduction of the master record.  The intent is

to insure that the batch was, in fact, produced

according to the approved formulation,

manufacturing instructions and controls.  The act

of computer transcription can generate errors.

The firm should check for such errors or otherwise

assure that no errors can occur.  During the

inspection the investigator can ask to see the

original approved, endorsed, master record and

compare it to the batch record.  The fact that the

batch record is a second or third generation copy

is not in and of itself objectionable provided it

is accurate.

            11.  NDA Considerations.  21 CFR 314.8 requires that a

supplement be submitted for changes in

manufacturing/control processes or facilities from

those stated in the approved NDA.  If a firm has

changed from a manual to a computerized system

under an NDA, that change should be covered by a

supplemental application.  If the change gives

increased assurance of product quality, then the

change can be put into effect before the

supplement has been approved.  However, such

supplements should state the anticipated

implementation date (which should be sometime

after the submission date) to allow reviewing

chemists the lead time needed to determine if the

type of change proposed is, in fact, of the kind

which may be implemented prior to approval.

 

GLOSSARY
 
 
ADDRESS                  A switch pattern which identifies the
                         location of a piece of data or a program
                         step.
 
ALGORITHM                A systematic procedure or equation
                         designed to lead to the solution of a
                         problem in a finite number of steps.
 
ALU                      Arithmetic Logic Unit; the circuitry
                         within the CPU which performs all
                         arithmetic functions.
 
ANALOG                   Continuous signal having a voltage which
                         corresponds to the monitored value.
 
APPLICATIONS             Term used to describe software written
                         to perform tasks on a computer.
 
ASCII                    American Standard Code for Information
                         change; a system used to translate
                         keyboard characters into bits.
 
ASSEMBLER                Program which translates assembly code
                         to executable machine code; e.g.
                         assembly code ADD becomes machine code
                         04.
 
ASSEMBLY CODE            Symbolics, a simple language; different
                         computers have different assembly codes.
 
ASYNCHRONOUS             Term used to describe the exchange of
                         information piece by piece rather than
                         in long segments.
 
AUXILIARY STORAGE        Storage device other than main storage;
                         disks and tapes.
 
BASIC                    Beginner's All Purpose Symbolic
                         Instruction Code; a high level language.
 
BATCH PROCESSING         Execution of programs serially with no
                         interactive processing.
 
BAUD                     The rate at which data is received or
                         transmitted in serial: one baud is one
                         bit per second.
 
BINARY                   The base two number system.  Permissible
                         digits are 0 and 1.
 
BIT                      Binary Digit; the smallest unit of
                         information in a computer, represented
                         as 0 or 1, off or on for a switch.
 
BOOT                     An initialization program used to set up
                         the computer when it is turned on.
 
BUFFER                   Part of memory used to temporarily hold
                         data for further processing.
 
BUG                      A program error.
 
BUS                      Electrical pathway by which information
                         flows to different devices.
 
BYTE                     A sequence of adjacent bits, usually
                         eight, operated upon as a unit; the
                         lowest addressable unit in a computer.
 
COMPILER                 Program which translates a computer
                         language into executable machine code.
                         A compiler translates an entire program
                         before the program is run by the
                         computer.
 
CP/M                     Control Program for Microcomputers; a
                         registered trademark of Digital
                         Research; an operating system.
 
CPU                      Central processing unit of a computer
                         where the logic circuitry is located;
                         the CPU controls the entire computer; it
                         sends and receives data through
                         input-output channels, retrieves data
                         from memory and conducts all program
                         processes.
 
CRT TERMINAL             Cathode ray tube; an input/output
                         device.
 
DATABASE                 Collection of data, at least one file,
                         fundamental to a system.
 
DATA SET                 Term synonymous with file.
 
DIGITAL                  Relating to separate and discrete
                         information.
 
DISK                     A circular rotating magnetic storage
                         device. Disks come in different sizes
                         and can be hard or flexible.
 
DISK DRIVE               A device used to read from or write to a
                         disk or diskette.
 
DISK OPERATING SYSTEM    DOS, a program which operates a disk
                         drive.
 
DISKETTE                 A floppy disk.
 
EPROM                    Erasable programmable read only memory:
                         switch pattern in circuit can be erased
                         by exposure to ultraviolet light.
 
FILE                     Set of related records treated as a
                         unit, stored on tape or disk; synonymous
                         with data set.
 
FIRMWARE                 A program permanently recorded, e.g., in
                         ROM.
 
HARD COPY                Output on paper.
 
HARDWARE                 Physical electronic circuitry and
                         associated equipment.
 
HEXADECIMAL              The base 16 number system.  Digits are
                         0, 1, 2, 3, 4, 5, 6, 7, 8, 9, A, B, C,
                         D, E, AND F.  This is a convenient form
                         in which to examine binary data because
                         it collects 4 binary digits per
                         hexadecimal digit.  E.g. Decimal 15 is
                         1111 in binary and F in hexadecimal.
 
INTEGRATED CIRCUIT (IC)  Small wafers of silicon etched or
                         printed with extremely small electronic
                         switching circuits; also called CHIPS.
 
INTERACTIVE PROCESSING   An application in which each entry calls
                         forth a response from a system or
                         program, as in a ticket reservation
                         system.
 
INTERFACE                A device which permits two or more
                         devices to communicate with each other.
 
INTERPRETER              A program which translates a high level
                         language into machine code one
                         instruction at a time.  Each instruction
                         in the high level language is executed
                         before the next instruction is
                         interpreted.
 
I/O PORT                 Input/output connector.
 
JOB                      Set of data completely defining a unit
                         of work for a computer.
 
K                        Symbol representing two to the tenth
                         power, 1024, usually used to describe
                         amounts of computer memory, and disk
                         storage, in bytes.
 
LANGUAGE                 Any symbolic communication media used to
                         furnish information to a computer.
                         Examples are PL/1, COBOL, BASIC,
                         FORTRAN, AND ASSEMBLY.
 
LOADER                   A program which copies other programs
                         from external to internal storage.
 
MACHINE CODE             Numerial representations directly
                         executable by a computer; sometimes
                         called machine language.
 
MAIN STORAGE             Term synonymous with MEMORY.
 
MAINFRAME                Term used to describe a large computer.
 
MEGABYTE                 1024K Bytes
 
MEMORY                   A non-moving storage device utilizing
                         one of a number of types of electronic
                         circuitry to store information.
 
MENU                     A CRT display listing a number of
                         options. the operator selects one of the
                         options.  Sometimes used to denote a
                         list of programs.
 
MICROCOMPUTER            A small computer (See MICROPROCESSOR).
 
MICROPROCESSOR           Usually a single integrated circuit on a
                         chip; logic circuitry of a
                         microcomputer; frequently synonymous
                         with a microcomputer.  A microprocessor
                         executes encoded instructions to perform
                         arithmetic operations, internal data
                         transfer, and communications with
                         external devices.
 
MINICOMPUTER             Medium sized computer.
 
MODEM                    Modulator - demodulation, a device which
                         accepts data from a computer, and sends
                         data to a computer, over telephone wires
                         or cables.  A half duplex MODEM can only
                         receive or transmit data at one time.  A
                         full duplex MODEM can receive and
                         transmit data at the same time.
 
MULTIPLEXER              A device which takes information from
                         any of several sources and places it on
                         a single line.
 
NETWORK                  A system that ties together several
                         remotely located computers via
                         telecommunications.
 
OBJECT CODE              Term synonymous with machine code.
 
OEM                      Original Equipment Manufacturer (i.e.
                         maker of computer hardware).
 
OPERATING SYSTEM         Set of machine language programs that
                         run accessories, perform commands and
                         interpret or translate high level
                         language program (usually written into
                         the ROM).
 
PARALLEL                 Term to describe transmission of data
                         eight bits (one byte) at a time.
 
PARITY BIT               An extra bit within a byte; used to
                         verify the coded information in the byte
                         itself.  The extra bit is either a one
                         or zero so as to make the total number
                         of ones in a byte equal either an odd or
                         even number (odd or even parity).
 
PERIPHERAL               A general term used to describe an input
                         or output device.
 
PROGRAM                  A collection of logically interrelated
                         statements written in some computer
                         language which, after translation into
                         machine code, performs a predefined task
                         when run on the computer.
 
PROM                     Programmable read only memory; once
                         programmed the switch pattern on a PROM
                         cannot be changed.  Special equipment
                         separate form the computer is usually
                         used to "burn in" the switch pattern.
 
 
                         communication between computers, i.e.
                         physical electrical links, message
                         format, message priorities, etc.
 
RAM                      Random access memory; internal storage
                         device containing volatile information
                         which can be changed; read-write memory.
                         When electrical power is cut off from a
                         RAM IC its memory is lost.
 
RECORD                   Collection of related data treated as a
                         unit.
 
SERIAL                   Term to describe handling of data one
                         bit at a time.
 
ROM                      Read only memory; internal storage
                         device in which information is
                         permanent.
 
RS-232C                  An Electronic Industries Association
                         (EIA) standard for connecting electronic
                         equipment; data is transmitted and
                         received in serial format.  This is an
                         interface standard that usually uses a
                         25 pin connector.
 
SOFTWARE                 Programs executable on a computer.
                         Programs are written in any number of
                         different languages.
 
SOURCE PROGRAM           High level language program which the
                         operator can read.
 
STORAGE DEVICE           A unit into which  can
                         be placed, retained and retrieved.
 
SYNTAX                   Required grammar or structure of a
                         language.
 
SYSTEM                   Term can refer to hardware or software.
                         For hardware it is the collection of
                         equipment that makes up the computer.
                         For software it refers to an integrated
                         number of computer programs to perform
                         predefined tasks.
 
TAPE                     A liner magnetic storage device rolled
                         onto a reel or cassette.
 
TELECOMMUNICATION        The devices and functions relating to
SYSTEM                   transmission of data between the central
                         processing system and remotely located
                         users.
 
TERMINAL                 A device, usually equipped with a CRT
                         display and keyboard, used to send and
                         receive information to and from a
                         computer via a communication channel.
 
UTILITY PROGRAMS         Special programs usually supplied by the
                         producer of the operating system.  They
                         perform general functions such as making
                         back up copies of diskettes and copying
                         files from tape to disk.
 
VALIDATION               The assurance, through testing, that
                         hardware or software produces specified
                         and predictable output for any given
                         input.
 
WORD                     One or more adjacent bytes conveniently
                         considered as an entity.  A word is
                         usually one to four bytes long,
                         depending on make of computer.
PROTOCOL                 Agreed upon set of standards which allow

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