Considerations for Medical Device Manufacturing

HKIE CPD Seminar on “Considerations for Medical Device Manufacturing – Optimization of materials, applications and sterilization and 2008 Healthcare Innovative Solutions by Advanced Medical Plastics” was held on 4 July 2008 in Hong Kong Productivity Council. The followings are summary of the seminar contents.

The first speaker is Mr. Kent Leung who is professional service specialist in 3M. He introduced the basic knowledge for medical device manufacturing such as sterilization, validation, commissioning and performance qualification, etc.

There are 7 principle of sterilization:
1. A process that kills all living forms including spores.
2. The process must have high penetration to reach the product.
3. The process must not destroy the product (non-destructive).
4. The process must be safe.
5. The process shall be easily monitored.
6. The process must be repeatable and controllable.
7. The process must keep the sterile state of the product afterwards (e.g. packaging).

Validation: Demonstrates and documents that a process does what it is supposed to do.


There are 3 common methods for microbiological qualification.
Method A: Survivor curve construction
Method B: Fraction negative method
Method C: Half-cycle method

All methods employed have the following assumptions:
- Organism population is homogeneous
- Process parameters, with the exception of time are constant from run to run
- A semi-logarithmic survivor curve exists
- Exposed & unexposed organisms respond similarly in the recovery medium


The second speaker is Mr. Simon Shih who is program manager – Greater China, SABIC Innovative Plastics (former GE Plastics). He introduced the material varieties and common application requirement, common sterilization methods, biocompatibility and regulations, etc.

The typical market needs are identified:
- Clarity
- Sterilization
- Lipid / chemical resistance
- Biocompatibility, Food contact compliance
- Regulatory

Clarity: clear or transparent resins are often employed for device.
When: Fluid flow is visually
View of contents is required
Colorability for aesthetic enhancements

Sterilization:
1. Radiation
2. Stream Autoclave
3. Dry Heat Sterilization
4. Ethylene Oxide (EtO)
5. STERRAD® sterilization system (~1hr – very long cycle time!)

Lipid resistance (Fat) typically considered to drug or blood carriers. Typically exposure from 3 to 4 days but new treatment technology may be from 6 to 7 days.
Chemical resistance included disinfectants / cleaner (e.g. bleach, ammonia, ethyl ketone, IPA, etc.)

Regulation (WEEE/RoHS) &
Biocompatibility, Food Contact Compliance (US FDA and EU Regulation)

Test protocol / methods:
- ISO 10993: Test standards established by ISO & FDA
- USP Class VI: Test standards established by US Pharmacopoeia
- Both test protocols are still valid.

Certified Lean Master study sharing (II)

In the previous section, we learnt how to define business case and value stream map of current state, as well as, Kaizen Blitz event in the process selected. During CLM section B course, the most important things that I explored were “Balanced Flow” and “Measurement”.

A game called “Red Bead Experiment” was played, which was originated from Deming. The game demonstrates one of golden rules that system variation (frequently referred to as random variation) is inevitably present in any process, operation or activity.

Where white beads represent goods and red beads represent defects.

Classmate is playing.

I also try the execrise.

After all classmates tried the game, the results were recorded as follows:

Mr. Mike Sheahan (our teacher) brought some interesting snacks from USA for tea time. (Remember the last time Lean Simulation using Lego!)

Quality of Rice

We visited Kwong Sun Hong on 30th May 2008. Kwong Sun Hong Limited was founded in 1935. It has been working hard to pursue the goal of supplying premium quality fragrant rice for local market consumption. In early 1980s, Kwong Sun Hong pioneered the modern way of packing rice with the aim of maintaining its quality to be as good as when it is freshly milled from the field for longer periods and with good stability. They launched the specially packed (CO2 treated) rice in 2 or 5 kilogram sizes in mid 1983.

We arrived Kwong Sun Hong Warehouse in Fanling. We found that the business of Kwong Sun Hong is not only for rice supply but also for warehousing facilities and logistic services to demanding local and international clients (e.g. DHL has distribution centre over there).


Mr. Foo explained the way to maintain the quality – smell, taste and texture – of rice (口感, 飯味). The environment for rice keeping should be 17oC and 70%RH.

The following interested information about rice was recorded during the visit:
香米 (Thai fragrant rice) – 軟身
大米 – 硬身
新花 – Depends on storage time (The only one harvest in Jan or Feb each year)
老花 – Depends on storage time (It is good for fried rice (炒飯).)
舊米 – 存放一年或以上 (Rice kept for longer than one year)

Traditional management system for rice stock was observed.

Then we took a photo in rice warehouse.

Study the rice packaging system.

A joint effort to prevent rice oxidation by Mr James Foo and Tokyo Automatic Machine Works 24 years ago had led to the existance of CO2 treated package rice. The research on the CO2 treated hibernated rice consequently turned out to be a success. Therefore, in mid 1983, Kwong Sun Food Products brought the CO2 treated Thai fragrant rice, which is packed in 2 and 5 kilos, for sale in local convenient stores and supermarkets.

It is very interesting that CO2 gas is filled into the rice package.

After one day, the package will shrink automatically and it looks like something after vacuum treatment.

HKSQ chairman (Dr. Albert Tsang) presented the souvenir to Mr. Foo.

There is a group photo taken in front of Kwong Sun Hong Warehouse.

Mr. Foo is very kind to give a souvenir (a pack of Thai Red Rice (泰國紅米) and Thai Fragrant Rice (泰國香米)) to each visitor.

For more information, please visit their website (http://www.kwongsun.com/).

Certified Lean Master study sharing

In order to improve our internal process, I have joined Certified Lean Master course organized by International Supply Chain Education Alliance (ISCEA). I would like to share something I have leant from the class.

Lean is the systematic elimination of waste.
Five Principles of Lean
1) Specify Value
2) Identify Value Streams
3) Create Flow
4) Leverage Pull
5) Seek Perfection

Our daily operation could be classified as Value Added (VA), Business Value Added (BVA) and Non-Value Added (NVA). Their definition is:
VA activities are necessary for meeting customer requirements.
BVA activities are not involved with meeting customer requirements, but are necessary (i.e. legal or internal policy).
NVA activities are not necessary for meeting customer requirements.

Example of Value Stream Mapping
7 types of waste (Muda)
1) Overproduction
2) Waiting
3) Transporting
4) Inappropriate Processing
5) Unnecessary Inventory
6) Unnecessary Motion
7) Defects

The most interesting section is Lean Simulation. Lean Lego Simulation (LLS) which has proven valuable for students to better understand lean principles and applications

In the beginning, I was a supplier and worked very easy because of kindly customer's Raw Material Receiving Dept.

During the production, we found that there were many stock (high inventory level) in raw material receiving dept.

and also in WIP (Head assembly, body assembly and final assembly).

Too far to transport the goods to QA dept. (Some defect happened during transportation.)

We drew the operation into Value Stream Mapping.

After that we re-designed the process using Kanban and reduced the inventory level. We ordered a specified and small quantities of raw material from supplier and sorting by QA and Receiving Dept.


Supplier cannot afford so many orders of small quantities. So the long lead time appeared.

See... The Head assemibly dept. was idle and enjoyed his drink to wait parts!

Very good practice!! We got experience from the real production line situation through this simulation.

At the end of workshop, I took a photo with the trainer "Mr. Mike Sheahan".

Visit two Mainland Medical Devices Manufacturers

HKSQ had visited two mainland factories for medical devices on 9th May 2008. They are Vincent Medical Mfg. Co., Ltd. and Providence Enterprise Limited. Recently, many mainland factories would like to transfer their capability to produce higher value product in order to improve their profit margin. This visit showed us how the household products and pump product manufactorers transferred into medical devices producers (Class I or IIa).

The first factory we visited was Vincent Medical Mfg. Co., Ltd. (group member of Vincent Raya Co. Ltd. - 永勝集團). Vincent manufactures various types of medical devices in its solely owned China factory. Their platform serves leading multi-national medical device companies with contract manufacturing services and their operation is ISO 9001 and ISO 13485 certified and supported with compliance to the US FDA’s GMP standard.

Before visit, their senior quality manager introduced the quality policy and risk management policy to us.



Introduction of different kinds of product:

HKSQ chairman (Dr. Albert Tsang) presented the souvenir to Mr. Otto To (GM).

Group photo in Vincent Medical Mfg. Co., Ltd.

Providence Enterprise Limited (香港匯進企業有限公司) is a full-service contract design & manufacturer dedicated exclusively to the production of highly engineered finished goods and electro-mechanical assemblies. Providence is a Founding Member of the Hong Kong Medical and Healthcare Device Association as well as a Corporate Member of the Hong Kong Auto Parts Industry Association. Their world-class results are assured by employing solid quality systems which is reflected in the certifications they have obtained, including ISO 9001, ISO 13485, ISO/TS 16949, ISO 14001 as well as 7S, SPC, FMEA and Six Sigma protocol.

Very beautiful door area.

Introduction video show

We observed a very good 5S practice around the factory. They called it 7S, the extra 2 S are Safety and Save.

HKSQ chairman (Dr. Albert Tsang) presented the souvenir to Mr. Albert Lee (CEO).

Group photo in Providence Enterprise Limited.

Biotech Lab General Requirement

The following information summarizes two types of laboratories requirements. The first one is a laboratory for microbiology test and the second one is for molecular biology test.

For Microbiology Laboratory, the facilities need to consider Biosafety Levels. WHO identified Risk Groups into 1, 2, 3 and 4. The table 1 is a classification of infective microorganisms by risk group.

Table 2 is relation of risk groups to biosafety levels, practices and equipment

Table 3 is summary of biosafety level requirements.

Code of practice
1. The international biohazard warning symbol and sign (Figure 1) must be displayed on the doors of the rooms where microorganisms of Risk Group 2 or higher risk groups are handled.
2. Only authorized persons should be allowed to enter the laboratory working areas.
3. Laboratory doors should be kept closed.
4. Children should not be authorized or allowed to enter laboratory working areas.
5. Access to animal houses should be specially authorized.
6. No animals should be admitted other than those involved in the work of the laboratory.

Fig 1. Biohazard warning sign for laboratory doors

Laboratory design and facilities for BSL 1 & 2.

1. Formation of aerosols
2. Work with large volumes and/or high concentrations of microorganisms
3. Overcrowding and too much equipment
4. Infestation with rodents and arthropods
5. Unauthorized entrance
6. Workflow: use of specific samples and reagents.
Examples of laboratory designs for Biosafety Levels 1 and 2 are shown in Figures 2 and 3, respectively.

Fig. 2 A typical Biosafety Level 1 laboratory

Fig. 3 A typical Biosafety Level 2 laboratory

The containment laboratory – Biosafety Level 3 is designed and provided for work
with Risk Group 3 microorganisms and with large volumes or high concentrations of
Risk Group 2 microorganisms that pose an increased risk of aerosol spread.

Fig. 4 A typical Biosafety Level 3 laboratory

The maximum containment laboratory – Biosafety Level 4 is designed for work withRisk Group 4 microorganisms. (It is not allowed in Hong Kong.)


For Molecular Biology Laboratory, the requirement to set up a PCR Laboratory is considered.

Development of the polymerase chain reaction (PCR) as a basic component of the molecular biology laboratory. The PCR laboratory typically is involved with activities that include sample preparation, PCR reaction assembly, PCR execution, and post-PCR analysis. Contamination prevention approaches are used in the PCR laboratory.

Fig.5 Outline of sample processing and analysis in a PCR laboratory.

Fig. 6 Organization of a PCR laboratory with separate pre- and post-PCR rooms.

Environmental Considerations

Air handling:
In the pre-PCR laboratory, there should be a slight positive pressure compared to the air in the connecting hallway. The post-PCR laboratory, in contrast, should be at slightly reduced pressure to pull air in from the outside and thereby prevent escape of amplicons from the completed PCR samples being analyzed inside the lab
UV irradiation:
It uses UV to sterilize the entire pre-PCR laboratory.
Protective clothing:
To further prevent PCR amplicons from leaving the post-PCR lab, each investigator should have a dedicated post-PCR lab coat. Additionally, each investigator should have a general molecular biology lab coat and a separate coat for pre-PCR.
Adhesive paper at lab entrances:
This approach effectively prevents trace amounts of dust and debris from entering the laboratory.

Reference:
1. Laboratory biosafety manual (Third edition) 2004: By World Health Organization
2. Setting Up a PCR Laboratory: By Theodore E. Mifflin (Department of Pathology, University of Virginia, Charlottesville, Virginia 22908)