Regulatory Expectations, Standards & Guidelines

Transcription

1 Regulatory Expectations, Standards & Guidelines Regulatory Requirements Pharmacopeias Good Automated Manufacturing Practice (GAMP) 21 CFR Part 11 and Annex 11 Consequences of Non-Compliance 22

2 Regulatory Expectations, Standards and Guidelines Most enterprises that require the services of analytical laboratories are subject to regulation of their activities. These regulations have been established to ensure public health and safety, protect the environment or ensure that the consumer is receiving products that conform to acceptable standards of quality. Regulatory Requirements The most important regulations for analytical laboratories servicing the pharmaceutical sector are the Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) regulations. An important requirement of these regulations is that any instruments used to test pharmaceutical products must be suitable for its intended purpose. An example of this requirement is the United States current good manufacturing practice regulations, Title 21 Code of Federal Regulations section (b) which states Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to ensure that components, drug product containers, 23

3 closures, in-process materials, labeling and drug products conform to appropriate standards of identity, strength, quality and purity. Laboratory controls shall include: (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and previsions for remedial action in the event of accuracy and/or precision limits are not met. Instruments, apparatus gauges and recording devices not meeting established specifications shall not be used. Other countries and jurisdictions have similar requirements. Pharmacopeias The pharmacopeia publications of various authorities such as the United States, European and International Pharmacopeias all contain chapters on high performance liquid chromatography. A particular point in these publications from the perspective of qualification is the inclusion of system suitability tests as an integral part of an analysis. This includes a number of criteria designed to assure the quality of each run, such as: Absence of peaks in sample blanks Repeatability of standard injections at the start of a run Recovery from a second standard solution Recovery from standard injections throughout the entire run Number of theoretical plates for the main peak 24

4 Tailing factor of the main peak Peak resolution of critical peaks The United States Pharmacopeia (USP) has also introduced chapter <1058> Analytical Instrument Qualification. This establishes three categories of instruments as defined below: Group A B Definition Standard equipment Magnetic stirrers No measurement capability Vortex mixers No requirement for calibration Centrifuges Conformance established through visual observation of operation Hot plates Standard equipment and instruments Balances Providing measured values and controlling physical parameters Refractometers Requires calibration Thermometers User requirements same as manufacturer's functionality and operational limits Ovens Conformance documented according to SOP through IQ and OQ C Examples Refrigerators ph meters Instruments and computerised analytical systems HPLCs User requirement for functionality, operational and performance are application specific Spectrophotometers Full qualification required Dissolution stations Gas Chromatographs 25

5 Good Automated Manufacturing Practice (GAMP) The International Society for Pharmaceutical Engineering (ISPE) has formulated a series of guidelines which provide an overall framework to the validation of automated manufacturing of pharmaceuticals. Of particular interest here are the guidelines on computerized systems. These guidelines have progressed through five versions (GAMP 1 GAMP 5) reflecting changes computing practice. GAMP advocates categorizing computerised systems according to their functional level as shown below for the two most recent versions. Category GAMP 4 GAMP 5 1 Operating System Infrastructure Software (OS, DB etc) 2 Firmware Not Used 3 Standard Software Non-Configurable Software 4 Configurable Software Configurable Software 5 Custom Software Customisable Software The rational for removing the category 2 from the GAMP 5 version is that firmware is still software and it can be accommodated within the other categories. GAMP also provides an overall qualification strategy for the different categories of software. 26

6 Category 1 Validation Strategy Ensure correct installation during IQ Implicitly test during OQ and PQ Record name, version number and any service packs 2 Consists of read only memory (ROM) Chips Treated as equipment and calibrated as appropriate 3 Qualify vendor Full qualification 4 Qualify vendor Full qualification Qualify bespoke configurations 5 Qualify vendor Full qualification Qualify bespoke configurations Validate bespoke code A HPLC would be categorised as GAMP 3 if it was a commercial off the self (COTS) instrument with no configuration as would be for a standalone non networked system. A networked system would probably be classed as GAMP 4. Both networked and not-networked systems could however contain GAMP 5 elements if bespoke software was installed. 27

7 21 CFR Part 11 & Annex 11 These pieces of legislation concern electronic records and electronic signatures as applied to healthcare products; 21CFR Part 11 applies in the US and Annex 11 applies in the EU. Both of these topics have the subject of books in this series and therefore only the more salient points which are applicable to the e-records created by HPLCs will be covered. The records created by HPLC instruments include: Results of stability and QC testing of finished pharmaceuticals products, APIs, in-process samples and raw materials To support this HPLC instruments will also create: Chromatograms Reports Summaries of results Instrument methods Injection sequences System suitability reports These records are required to be maintained by GMP and GLP regulations and therefore, if these records are maintained in electronic 28

8 format, the provisions of 21 CFR Part 11 and Annex 11 apply. Indeed as the electronic record would normally the original record it could be argued that chromatographic records must be maintained in electronic format. To be compliant the HPLC system must be capable of: Restricting access to authorised individuals, such as Users logging in under their individual accounts System should be capable of limiting the number of unsuccessful log-in attempts (typically three) after which the user is locked out Record unauthorised log-in attempts and alert security management Passwords should be changed at established intervals, preventing reuse of passwords Passwords should comply with complexity policies, such as minimum length Users should log-off of the system when finished use or alternatively an auto log-off facility may be employed Providing a computer generated audit trail To track changes to methods, sequences and number of processing attempts Should identify who made any changes together with the reason for the changes and the time they were made Security of data files Must be capable of preventing unauthorised deletion or 29

9 manipulation of data files Must be capable of identifying, logging and reporting unauthorised attempts at data file deletion or manipulation Date time stamps Should be accurate to within ± 1 minute and should be linked to a defined standard clock such as NRC, NPL or NIST Should include time zone information such as UTC, BST or EST Consequences of Non-Compliance The objective of qualifying any analytical instrument is to secure a high level of confidence that the instrument will consistently produce scientific data that conforms to appropriate quality criteria. Conversely a failure to adequately qualify an instrument would mean that confidence is lacking. This would mean that decisions taken which depend on such data would be questionable and could result in for example, sub-standard products reaching the consumer. Such products could present significant health and safety risks. In addition such products could be deemed to be adulterated resulting in the need for recall of product causing a loss of revenue for the manufacturer. In addition, the introduction of adulterated products will result is regulatory action, such as audit observations, warning letters, consent decrees and criminal prosecutions. All of these can incur significant expense for a manufacturer. One company had to pay $100 million to the US 30

10 government, employ expert consultants at an estimated total cost $475 million and lost about $250 million in annual sales. There is also the very real possibility of civil litigation. In one case a pharmaceutical company paid out over $10 billion to consumers who were injured by one of its drugs. 31