Medinol Process Insights

This document outlines the use of Statistical Process Control (SPC) at Medinol Ltd. for the purpose of controlling and maintaining process capability and yield, controlling product characteristics, and for lot release. Statistical Process Control is a continuous process at Medinol. The scope of the SPC process is reviewed and updated as warranted by the developing process maturity and by changes in the product range. The purpose of the yield analysis is to identify low yield steps in the manufacturing process, find their root causes, and trigger improvement processes.

The scope of this document encompasses all manufacturing and quality control activities carried out at Medinol’s Jerusalem manufacturing plant. This document does not encompass products in the design cycle.

Definitions/Acronyms:

• Control chart: A chart with control limits, showing the behavior of a parameter in time.

• Control limits: Also known as Action limits or SPC limits.

• CPI: Critical Process Indicators.

• CYI: Critical Yield Indicators.

• DCC: Documentation Control Center.

• Monitor: A control chart with defined action limits, that establishes the validity of an operation or machine.

• OOC: Out of Control.

• OOS: Out of Specification.

• Ppk: Critical Process Performance indicator.

• Priority: Manufacturing Control Software as used by Medinol.

• Process indicators: Parameters which are understood to be indicative of the quality of the process.

• Product indicators: Parameters which are understood to be indicative of the functionality of a product.

• Product line: A suite of individual products that is manufactured using essentially the same manufacturing process and is validated as a whole.

• SPC: Statistical Process Control.

• Standard deviation.

Responsibilities:

The Manufacturing Top Level Management is responsible for the definition and maintenance of Critical Process Indicators and their periodical review in statistical review meetings, the filing of SPC meeting minutes and presentations, and the definition, validation, and maintenance of Machine Monitors used to establish Process stability. The Manufacturing Top Level Management, the Supply Chain Top Level Management, and the R&D Top Level Management are jointly responsible for reviewing and ratifying the proposed monitoring schemes and ensuring their implementation in the manufacturing process to improve the SPC. The Validation Leader Process Engineer is responsible for supporting the inclusion into Priority of any and all data collection schemes required to support the proposed and ratified indicators. It is the responsibility of the Documentation Control Center Group Manager to archive the CPI review reports and the lists of Critical Process Indicators. The Supply Chain Top Level Management is responsible for the definition and maintenance of Critical Yield Indicators and their periodical review in statistical review meetings.

Procedure:

Statistical Process Control at Medinol is defined as the tracking of performance over time, for any parameter, whether control limits are applied or not. SPC may be defined for manufacturing yield as an indicator of manufacturing stability, process indicators which predict the ability of the product to function as required; these include machine monitors, process monitors, and product testing. Product indicators such as complaint rate, and system indicators which reflect the performance of key quality systems may also be included. SPC Section Owners may be appointed as appropriate, with suggested ownership for manufacturing yield by the Supply Chain department, for system indicators by QS, and for Machine Monitors and Process Monitors by the Manufacturing department. Where appropriate, multiple types of the same product may be combined in a single control chart. SPC limits for process indicators, where applied, shall be defined to suit the distribution, and the process for their determination shall be documented by the Manufacturing department in a report, approved by the Manufacturing Top Level Management and QS representative and filed in the DCC. Following SPC limits determination, an SPC Reporting Control Chart form will be issued for each commercial lot of the product and used to check for Out of Control data before lot release, as described in SOP 908000034 (not applicable to analytical testing for drug characteristics of combination products).

Generally, tentative SPC limits will be set up to six months from release testing of the first commercial production lots but no later than 1 month after the second quarterly SPC meeting presenting data for commercial lots. These tentative limits will be based on NLT 5 initial commercial production lots.

These tentative limits will be based on the initial commercial production lots, on PV data and/or previous similar product data. Tentative SPC limits may be set at more than +/- 3s, due to insufficient data on lot-to-lot variation.

After the accumulation of sufficient lots, the SPC limits will usually be defined on the basis of +/- 3s, though other limits may apply for parameters which are not distributed normally.

After the accumulation of NLT 30 lots, limits will generally remain constant, unless warranted by exceptional circumstances (e.g. process changes).

Critical Process Indicators (CPI):

The Manufacturing Top Level Management is responsible for defining and maintaining a separate list of CPI for each product line. These CPI lists are controlled documents. The lists form the core of the quarterly SPC review as they pertain to product and process performance, indicating which parameters require reporting at each review meeting. The CPI list can be updated if new potential failure modes are identified or if a specific indicator is no longer considered critical, based on long-term analysis by the Manufacturing department.

For new products, a tentative list of all monitors will be made during the definition of the Initial Manufacturing Process Specification following design verification. The CPI list will be generated from this tentative monitor list by the Manufacturing department no later than six months post product launch. At that time, it will be reviewed by the SPC review meeting and approved. The main consideration in defining the CPI list is the degree of insight the monitor provides regarding potential failure modes with high clinical risk.

Critical Yield Indicators (CYI):

The Supply Chain Top Level Management is responsible for defining and maintaining a list of CYI for marketed products. The CYI list, a controlled document, constitutes the core of the quarterly SPC review as it pertains to yield performance. It will indicate which parameters require reporting at each review meeting.

SPC Review:

SPC review meetings will be held on a quarterly basis with participation from the Manufacturing department, Supply Chain Top Level Management, manufacturing area managers, QC and QS personnel, relevant R&D representatives, and department managers. Meeting summaries will be saved in an electronic folder and in hard copy. The SPC meeting of the last quarter of each year will review the whole year's manufacturing volume. In case of low manufacturing volume, the specific low volume product will not be presented. The minimal content of the reviews is defined in the CPI and CYI lists.

During the SPC review, all relevant CPI control charts, any Out of Specification conditions and their responses, any Out of Control conditions and the insights generated, and during annual reviews, long-term comparisons may be added along with CYI charts. If undesirable conditions are observed during the review of the CPI control charts that require a process improvement, then a Corrective and Preventive Action will be opened.

A Ppk review will be added to the SPC review, providing a concise summary of the Ppk of all validated process SPC charts. This review will include only products for which more than five lots were produced in the last quarter. A Ppk better than 1.33 is considered good and better than 1.0 is sufficient. A Ppk that deteriorated to below 1.0 will trigger a process investigation, which will be presented at the Ppk review. If the investigation indicates that there is cause for concern and improvement is required, further follow-up will be controlled by a CAPA.

The SPC review meeting minutes will be issued to the attendant managers for remarks and will be filed by the Manufacturing department and the Supply Chain department. Similarly, the SPC review presentations will be filed in the SPC meetings folder in the shared drive. CPI and CYI checklists, confirming that all critical indicators were reviewed, will be prepared after each SPC review meeting, approved by the Manufacturing Top Level Management and the Supply Chain Top Level Management, and filed by the Documentation Control Center Group Manager.

SPC Release:

After amassing sufficient data and maintaining a manufacturing volume of at least twenty lots per month for a product line, if the Ppk values for individual release test parameters are greater than 1.33, these release tests may be discontinued, and lots may be released without release tests as long as manufacturing conditions are stable and a representative process monitor is established. Such transitions, their justification, and their mechanism will be processed through the Engineering Change Request/Engineering Change Order mechanism with regulatory inputs as required.