1 Design and Construction
The ISPE baseline guide volume 5 "Commissioning and Qualification" gives a very pragmatic system to ensure that systems are "fit for purpose". This guide recommends undertaking an assessment to separate critical equipment from non-critical. An example would be that cooling water services should be designed according to Good Engineering Practice (GEP) while the temperature probe used for a critical processing parameter should be fully qualified using an enhanced design review.
Materials of construction should be indifferent towards the process materials in order to minimise potential reactions of such materials (e.g. iron with salt solutions giving rust) to avoid formation of impurities that could adversely affect product quality It also means that the materials should not shed extraneous matter into the process and they should not leach materials into the process. Some forms of polymer or filter cloths would be examples of this type of material.
If equipment has been qualified over a narrow range and is capable of operation over a wider range then before use it should be re-qualified over the wider range. Most manufacturers design equipment for use in multi-product facilities. From this perspective it would be advisable to purchase equipment that has versatility and is able to cover a wide range of requirements. It should be ensured that the equipment is able to operate correctly for each particular process. (Reference: Chapter 12.3, PQ). An example of this may be a temperature probe that can monitor temperatures over a range -20 to 150 °C but that can also be tuned to enable a reaction temperature of just +/-2 °C to be accurately monitored without the tolerance of the instrument being greater than the range.
As built drawings should be maintained and updated as part of change control. Failure to do this could lead to safety and quality issues. Major Equipment can be identified using as built Pipe and Instrumentation Drawings (P&IDs) with pipes also identified in the plant as well.
An approved list of lubricants etc can help to ensure that the correct materials are used. Each material should be reviewed for chemical content and potential quality impact. The FDA web page can be searched for approved food grade materials. These can also be specified to equipment vendors during design of new equipment. Increasingly dry seals for agitators are being used to overcome this type of issue.
The use of closed or contained equipment applies to the final steps and isolation of the API. For most chemical synthesis this would be a safety requirement in any case. It needs to be stressed that the are no requirements for room specifications for non-sterile APIs at any stage of processing. It is prudent however to increase precautions as the final API step is approached. Early steps requiring materials to be charged in an open plant (inside) environment may also require controls but only for operator protection provided basic cGMP control is in place. See also Chapter 7.4 for additional advice for sampling activities.
Contents of cleaning instructions
2 Equipment Maintenance and Cleaning
A good preventative maintenance program is very important in reducing the number of equipment breakdowns that could cause impact upon product quality, schedule and maintenance costs. This is particularly important for critical equipment that needs regular attention to prevent failure.
See the APIC Documents "Cleaning Validation in Active Pharmaceutical Plants - Policy, 1999" and "Cleaning Validation in Active Pharmaceutical Plants - Guidance" for practical advice on this subject.
Many companies make the mistake of allowing engineers to classify any measuring device as a critical device. Each device should be reviewed to assess what the impact would be of failure or incorrect readings.
Classifying instruments as:
- critical GMP-CPP (critical process parameter) or CQA (critical quality attributes) controlling equipment,
- GMP = direct quality impacting,
- GEP - indirect or non-quality impacting.
Undertaking this task will allow the critical measuring equipment to be very tightly controlled and not submerged by the vast numbers of instruments that are used within an API site. Many companies use outside agencies for calibration. The equipment user is responsible for ensuring that the outside agencies are competent to undertake the calibration to the appropriate standards.
Critical instruments need to be calibrated by using standards traceable to certified standards.
A very good approach is to calibrate prior to start up and then at defined intervals according to the history of calibrations built up with experience. A good idea when starting is to have regular reviews of such data to collect supporting data to define appropriate calibration frequencies (shortened or expanded, based on collected data and experience), re-evalution periods etc. These reviews are also a very helpful tool to observe any trend and therefore to be able to react before instrument failure occurs.
A procedure should exist to ensure that instruments not meeting calibration criteria are not be used. It is for this reason that tolerance ranges and calibrations should be appropriately selected for the process to ensure that non-impacting failures of calibration criteria are not routinely observed.
The calibration of critical instruments must be appropriate to prevent unnecessary non-added value investigations into minor failures that could never impact upon quality.
4 Computerized Systems
Computerised systems have a very high profile and require an extremely thorough validation approach. It is an area of high inspector interest especially for suppliers of the US market. Reference: Computer validation guideline by APIC which provides some pragmatic guidance in an area which often involves large amounts of paperwork with too often distressingly low value. Another reference is GAMP 4 .
IQ and OQ of computer hardware and software are often treated entirely separately from equipment IQ/OQ. It may be very advantageous to combine the two especially when the two are intrinsically dependent or linked.
Commercially available software by the nature of economic viability and wide-scale usage will reasonably have determined whether the software is fit for purpose. The GAMP guidance is very useful in determining the testing requirements.
Basic security measures such as access control and user passwords will enable most systems to operate in a compliant manner. Electronic date, time and user stamps are becoming more and more prevalent as industry becomes familiar with the requirement for audit trails. A common problem however is that the audit trails are poorly designed and do not allow searching on the basis of reason for change, date, operator etc. This area is a very significant area of interest for inspectors.
An additional check does not automatically mean a second operator that must watch the figures being entered just that the value should be checked. Double data entry where the system checks each entry against the previous entry to ensure there has been no transcription error. This has been found to be a very effective error reducing mechanism.
The handling of incidents is analogous to equipment logs. Again some form of categorisation and system should be used to ensure that non-value added or non-quality impacting information is not being collected and investigated.
Change control should be appropriate to the criticality of the system. GEP systems should not require quality review.
For critical systems a backup system should be available. A server system with automatic back up is ideal but read only CDs can be as effective. It should be noted that it is very difficult to make local PC systems secure.
Materials used for equipment (that come into contact with the product) should not have any impact on the product quality. A reproducible cleaning procedure based on detailed cleaning instructions is required to guarantee that no subsequent products are contaminated. The qualified status of the equipment is maintained by regular maintenance and calibration. Computer system validations are required for computer systems used in the GMP environment.