Canada guidance for PV of moist heat sterilization.docx

1、Canada guidance for PV of moist heat sterilizationProcess validation: moist heat sterilization for pharmaceuticals (guidance from Canada)1. IntroductionThe Health Products and Food Branch Inspectorate (HPFBI) of Health Canada recognizes that terminal moist heat sterilization, when practical, is pres

2、ently considered the method of choice to ensure sterility. For the purpose of ensuring sterility, all aqueous-based sterile products are subject to terminal moist heat sterilization, with the following exceptions: Instances where terminal moist heat sterilization is not practical, e.g., product degr

3、adation. Such instances are fully evaluated and documented. And for aseptic processes that exclude human intervention e.g., robotics, form-fill-seal and barrier system, may be employed in lieu of terminal moist heat sterilization providing that validation data demonstrated equivalence.This document

4、is intended to provide manufacturers of pharmaceutical dosage forms with guidance to establish the scientific effectiveness of moist heat sterilization processes, as required in Sections C.02.004, C.02.005, C.02.007, C.02.011 and C.02.029 of the Food and Drug Regulations. The intent of this document

5、 is not to detail specific procedures or define elaborate mathematical principles which are critical to the validation process, as such information is readily available from other sources; rather, this guideline is intended as an outline of the elements in moist heat sterilization processes requirin

6、g evaluation, and describes approaches to effectively accomplish this goal in a manner which is acceptable to the HPFBI of Health Canada. Other approaches which achieve equivalent results may also be acceptable.The section 17 of this guideline specifies the minimum documentation required to certify

7、that moist heat sterilization processes have been thoroughly evaluated and are adequately controlled and validated. Such documentation, aside from being invaluable to the manufacturer, is essential to the specialists of the HPFBI for the purpose of inspection and submission evaluation.This guideline

8、 is applicable to moist heat sterilization processes only. While the principles outlined in this document are shared with other methods of sterilization, those processes require control and assessment of different parameters. It must be recognized that, regardless of the sterilization process, the c

9、ontrol of manufacturing environments and good manufacturing practices which provide barriers to microbial contamination remain of utmost importance.Environments for the manufacture of drugs subject to terminal sterilization:Drugs subject to terminal moist heat sterilization may be formulated in a gr

10、ade C environment, provided that the formulated bulk is immediately subjected to its subsequent processing step, e.g., filtration, sterilization, so as to maintain low microbial and particular counts. Formulating may take place in a grade D environment if additional measures are taken to minimize co

11、ntamination, such as the use of closed systems of manufacture.Parenterals are filled in an aseptic area of at least a grade B environment or in a grade A zone with at least a grade C background before terminal moist heat sterilization.Non-parenterals may be filled in a grade C environment before ter

12、minal moist heat sterilization.Note: The limits for the microbial contamination and for the maximum number of particules, in the at rest and in operation states, in relation to different grades of air standards, are defined in the HPFBI Revised Guidance for section C.02.029 (Sterile Products) of the

13、 Good Manufacturing Practices Regulations.2. Validation ApproachesThe validation of moist heat sterilization processes may be performed using any of the three strategies outlined below. The approach selected should be appropriate and adequately supported. It should be stressed that the integrity of

14、the container/closure system be established prior to validating the sterilization process to ensure that an appropriate container/closure system has been selected.2.1 Prospective ValidationThis approach applies to new or modified processes and new equipment. The studies are conducted, evaluated, and

15、 the process and equipment system certified prior to initiating routine production.2.2 Concurrent ValidationThis approach applies to existing processes and equipment. Concurrent validation studies are conducted during regular production and should only be considered for processes which have a manufa

16、cturing and testing history indicating consistent quality production. Reworks and failures indicate potential inconsistencies in the process and should be evaluated for effect on the reproducibility of production prior to establishing validation protocols.Although suitable records may not be availab

17、le for the installation of equipment, lack of this data may not compromise the balance of the studies.2.3 Retrospective ValidationThis approach can only be applied to existing products, processes and equipment and is based solely on historical information. Normal processing records generally lack su

18、fficient detail to permit retrospective validation.a. It must be established that the process was not modified and that the sterilizing equipment is operating under the same conditions of construction and performance as documented in the records to be considered. Maintenance records and process chan

19、ge control documents should be available to support these claims.b. Periods in which failures occurred should not be excluded. The incidence of failures or reworking attributed to unsatisfactory processing indicates inconsistency in the process. There should be an evaluation of these conditions for

20、the period to be used for validation.c. The manufacturing, maintenance and testing data should be capable of demonstrating calibration of equipment and devices, and establishing uniformity and consistency of sterilizing conditions equivalent to those required in Sections 7 through 14.Note: Additiona

21、l detailed information in relation to different validation approaches is provided in the HPFBI Validation Guidelines for Pharmaceutical Dosage Forms.3. Validation Protocol Development and ControlEach stage of the evaluation of the effectiveness and reproducibility of a sterilization process should b

22、e based on a pre-established and approved detailed written protocol, developed in accordance with the validation approach chosen as outlined in Section 2. A written change control procedure should be established to prevent unauthorized change to the protocol or process and restrict change during any

23、 phase of the studies until all relevant data are evaluated.The protocol should specify the following in detail:3.1 the process objectives in terms of product type, batch size, container/closure system, and probability of survival desired from the process;3.2 pre-established specifications for the p

24、rocess which include the cycle time, temperature, pressures and loading pattern;3.3 a description of all of the equipment and support systems in terms of type, model, capacity and operating range;3.4 the performance characteristics of each system, sub-system or piece of equipment in Section 3.3; per

25、formance characteristics including pressure gauge sensitivity and response, valve operation, alarm systems functions, timer response and accuracy, steam flow rates and/or pressures, cooling water flow rates, cycle controller functions, door closure gasketing, and air break systems and filters;3.5 fo

26、r new equipment: installation requirements and installation check points for each system and sub-system;3.6 for existing equipment: the necessary upgrading requirements or any compensatory procedures; justification for alternate procedures should be available;3.7 methodology for monitoring the perfo

27、rmance of equipment and of the process as outlined in Sections 7 through 14;a. all laboratory testing methodology;3.8 the personnel responsible for performing, evaluating and certifying each stage of the validation protocol and for final evaluation prior to certification of the process.4. PersonnelD

28、ocumented evidence of the experience and training of all personnel involved in validation studies should be maintained.4.1 Qualified personnel should ensure that the validation protocol and testing methodology are developed in a sound engineering and scientific manner and that all studies are proper

29、ly evaluated and certified.4.2 All personnel conducting tests should be trained and experienced in the use of the equipment and measuring devices.4.3 Engineering/mechanical personnel should be qualified in the operation and maintenance of sterilizers and support systems.5. Data Review and Study Cert

30、ificationAll information or data generated as part of the validation protocol should be evaluated by qualified individuals against protocol requirements and judged as meeting or failing the requirements. Written evidence supporting the evaluation and conclusion should be available.5.1 The evaluation

31、s should be performed as the information becomes available.5.2 If evaluations show that the validation protocol criteria were not met, the impact on the process and the suitability of the protocol parameters should be investigated and the conclusion documented.5.3 Failure to adhere to the procedure

32、as laid down in the validation protocol must be considered as potentially compromising the validity of the study itself, and requires critical evaluation of the impact on the study.5.4 The final certification of the validation study should specify the established process parameters. This information is required for post-validation monitoring as described in Section 15.6. Laboratory Considerations6.1 All laboratory tests, including D value analysis, should be performed by a competent laboratory. The laboratory should have detailed methodology and procedures covering all laboratory functi