PIP breast implants - TGA update, 2 April 2012
PIP breast implants - a summary
PIP breast implants are medical devices manufactured by a French company, Poly Implant Prothèse (PIP).
PIP breast implants are known to have been used in Australia from September 1999 until April 2010, when non-implanted PIP breast implants were recalled from the market following advice from the French regulator (AFSSAPS) that the manufacturer had used unapproved materials in making these devices which may affect their safety and performance.
An updated Australian perspective was published by the TGA on 23 March 2012.
In light of international concerns about the safety and performance of these implants, the TGA has been conducting an extensive investigation into PIP breast implants, and a considerable amount of evidence has now been collected. This investigation includes laboratory testing of the PIP breast implants and a progress review of this on-going testing program is provided below.
Testing undertaken by TGA to date has not found evidence that the risks involved with the use of PIP breast implants are any greater than those for any other brand of silicone gel-filled breast implants.
The regulation of breast implants
The TGA is Australia's regulator of therapeutics goods. Breast implants are regulated by TGA as 'high risk' (Class III) medical devices. The TGA determines which medical devices may be legally marketed in Australia by assessing the likely risks and benefits of a particular medical device against a set of 'Essential Principles', and allowing a medical device to be marketed where the likely benefits outweigh the likely risks. The intensity of the assessment increases with the degree of likely risk.
For implantable medical devices such a breast implants, the legal authority of the TGA in relation to the recall of faulty goods is limited to the recall of devices that have not yet been implanted in a person. TGA has no authority to direct a surgeon to remove a device from a person, or to direct a person to have such a device removed.
Where an implantable device is recalled for a reason that may have an impact on the health of a person who has that device implanted, the role of the TGA is to ensure that factual information about the reason for the recall and the potential implications for patients who already have such devices (a 'safety alert') is available to help doctors and their patients determine the appropriate clinical management.
Progress review of on-going TGA Laboratory testing program
Following advice from the French regulator (AFSSAPS) that the French company Poly Implant Prothèse (PIP) had used unapproved materials in making silicone-filled breast implants which may affect their safety and performance, in consultation with other international regulators TGA decided to conduct its own tests so that important information would be available to Australian doctors and patients.
The TGA testing program builds on findings from testing reported by the AFSSAPS (pdf,1.72Mb), who carried out mechanical, toxicity and chemical tests, and the regulator in the UK (Medicines and Healthcare products Regulatory Agency - MHRA) who commissioned toxicity tests. The TGA has focused its testing program on the areas of concern that were reported by AFSSAPS.
What is in a silicone breast implant
Silicone breast implants
A silicone gel-filled breast implant is a silicone elastomer shell (sac) that has been filled with a cohesive silicone gel. The thickness of the shell varies around the implant, but is typically between 0.5 and 1.0 mm thick. The surface of the shell can be manufactured to be smooth or have a textured (rougher) characteristic. There is a hole at the back of the shell through which the filler silicone gel material is introduced.
The gel in all silicone gel-filled implants is a lightly cross-linked polydimethyl siloxane (silicone) matrix, which contains a viscous silicone fluid (oil) that is not chemically bonded within the gel. The gel is cohesive and has the consistency of a well-set jelly. The gels are formed by filling the outer shell of the implant with a combination of chemically reactive and un-reactive silicone oils, sealing the shell with a patch and curing (heating for a specified time) the entire implant.
PIP breast implants
AFSSAPS has reported that there are at least three different formulations of filler gel used in PIP breast implants. The different formulas are detailed in the table below. According to AFSSAPS, the authorised gel was manufactured with NUSIL 3MED6300 gel, while the unauthorised gels were manufactured using a combination of other brands of silicone raw materials, with two different formulations identified as PIP1 and PIP2. Apparently, PIP1 was manufactured prior to 2008 and PIP2 from the beginning of 2008.
It is not clear when NUSIL was used to manufacture the gel used in PIP breast implants, but it appears that this gel was used in micro-textured PIP breast implants after the middle of 2006, although this type of implant does not appear to have been supplied in Australia.
|NUSIL||PIP 1||PIP 2|
|Manufacturer of raw materials||Nusil|| |
Bluestar - Rhodorsil product
Momentive - Silopi product
Bluestar - Rhodorsil product
Momentive - Silopi product
|Formula||NUSIL 3 MED 6300||100%||Silicone oil trimethylated Silopi (W1000) or Rhodorsil (H47V1000)||94.3%||Silicone oil trimethylated Silopi (W1000) or Rhodorsil (H47V1000)||90.2%|
|Vinyl terminated silicone oil Silopi (U165)||4.4%||Vinyl terminated silicone oil Silopi U165||8.3%|
|Rhodorsil RTV 141 Part A||1.1%||Rhodorsil RTV 141 Part A||1.1%|
|Rhodorsil RTV 141 Part B||0.2%||Rhodorsil RTV 141 Part B||0.4%|
|Ratio of Rhodorsil RTV A:B = 5.5 compared to manufacturer's recommendation of 10||Ratio of Rhodorsil RTV A:B = 2.75 compared to manufacturer's recommendation of 10|
TGA Laboratory testing plan
Range and number of samples
The TGA testing program has used samples from the broadest cross-section of batches and models of PIP breast implants available to the TGA, and has also tested batches of other brands of breast implant for comparison.
The TGA is also testing different silicone raw materials that have been used in the manufacture of the silicone gel in the PIP breast implants.
To date, TGA has received 19 different batches (29 samples), from the Australian market, and 5 batches (23 samples), from overseas, of PIP breast implants. Findings from testing these batches build on the testing of around 30 batches by AFSSAPS and the results reported by the MHRA.
By way of example, AFSSAPS used 5 batches in an 'elongation test' and 4 batches in an 'intradermal irritation test'. The TGA further investigated those tests by testing 13 batches in the elongation test and 7 batches in the intradermal irritation test (in studies TGA commissioned both in Australia and in Europe).
To date, the TGA has also conducted tests on 14 PIP breast implants that have been surgically removed (explanted) to provide further evidence that will assist with determining the overall quality and safety of the product. The TGA is not aware of any regulator from any other country that has reported results from testing explanted PIP breast implants.
Since the original advice was that PIP breast implants had been manufactured with unauthorised silicone gel filler, initial testing focussed on establishing the physical and mechanical properties, as well as the toxicity of the implants. Subsequent reports, particularly in February and March 2012, presented clearer details of the findings from laboratory testing commissioned by AFSSAPS. Consequently, TGA focussed its laboratory investigations on:
- the irritant potential of the shell and gel used in PIP breast implants
- chemical toxicity, including presence of metals
- mechanical characteristics of the shell, with special regard to the tensile elongation test
- mechanical characteristics of the filler gel, with special regard to the firmness and cohesiveness of the gel
- chemical analysis of the gel, especially determining the presence of low molecular weight silicones
- other physico-chemical features of the gels, especially thermogravimetric behaviour
- investigation of explanted PIP breast implants.
These studies are summarised in the Table below.
|Chemical analysis|| |
|Physico-mechanical tests|| |
|Testing on explanted PIP implants|| |
Limitations to testing
Testing provides a measure of the compliance of a particular sample with specified quality criteria. The quality of the sample is taken to be reflective of the batch from which the sample is drawn. However, the samples tested may not be representative of other batches of the product. Nevertheless, it does provide a very useful support to other measures by providing an immediate assessment of quality of the portion or the sample of the batch tested.
Prudent interpretation of testing results is necessary as there are limitations to the testing program, especially relating to a lack of unambiguous controls, presence of multiple gel formulations, lack of manufacturing batch documentation, and a lack of samples manufactured prior to 2008.
The TGA laboratory testing program is not a substitute for the testing that a manufacturer is required to carry out to demonstrate the overall quality and safety of a product.
To date, the TGA has hosted 3 meetings (19 January, 9 February and 8 March 2012) of the international testing panel for PIP breast implants (ITPP). The role of the ITPP is to discuss laboratory testing of PIP breast implants through teleconferences and on-going email exchange.
Findings from testing
- While AFSSAPS reported a 'potential irritant' finding for the filler silicone gel, this is not consistent with testing results from studies commissioned by the TGA. Two different laboratories (in Australia and Europe) carried out tests in accordance with the international standard and results from both laboratories indicated that the gel and the shell of tested PIP breast implants were non-irritant.
- Testing by the TGA, MHRA and AFSSAPS has not shown chemical toxicity to living cells (cytotoxicity). Furthermore, testing by AFSSAPS and MHRA has not shown toxicity to DNA within the genetic machinery of the cell (genotoxicity).
- Consistent with reports by AFSSAPS, the TGA has noted that there is variability in the physico-chemical characteristics of different batches of PIP breast implants.
- Questions have been raised about the amount of small molecular weight silicones (D4-D6 siloxanes) that may be present in unauthorised gels. To date, chemical testing indicates that the amount of these siloxanes in PIP breast implants is not a safety concern.
- Testing has not identified any metals in the tested PIP breast implants that are at a level of concern.
- The TGA testing did not identify problems regarding shell integrity, although AFSSAPS reported failures related to the tensile elongation test.
- While TGA investigations generally found filler gels to be suitably firm and cohesive, some PIP breast implants appear to be less firm.
Intra-dermal irritation study
TGA commissioned intra-dermal irritation tests on PIP breast implants in laboratories both in Australia (Laboratory A) and Europe (Laboratory B). The purpose of this study was to assess the potential of polar (saline) and non-polar (oil) extracts of shell and gel components of PIP breast implants to produce irritation following intra-dermal injection into rabbits. Another brand of implant (Brand M) that contains the authorised gel was used as a control. The findings of the study were:
- Laboratory A: All batches non-irritant
- Laboratory B: All batches non-irritant
|Batch||Expected Gel||Component||Extraction Conditions||Laboratory A||Laboratory B|
|6009626||Brand M||Shell||37°C; 72hrs||0||0||N||N|
Cytotoxicity tests measure whether there are chemical toxins in the material that are toxic to cells. To date, testing by AFSSAPS, MHRA and TGA has not shown that the gels contain such chemical toxins. Nevertheless, given that the manufacturer has used unauthorised gels and different formulations of those gels, the TGA is continuing to do cytotoxicity tests in order to increase the pool of results on PIP breast implants, as well as on the raw material silicone oil used to make the gels.
|25109||PIP2||Shell & Gel||0|
|36709||PIP2||Shell & Gel||0|
|56206||PIP1||Shell & Gel||0|
|01809||PIP2||Shell & Gel||0|
Chemical identification and chemicals of concern
The silicone gels are being chemically fingerprinted using Fourier transform infrared spectroscopy (FTIR) and chemically profiled using gas chromatography–mass spectrometry (GC-MS), thermogravimetric analysis (TGA) and gel permeation chromatography (GPC).
FTIR has not provided useful differences to distinguish gels. Tests for low molecular weight silicones using GC-MS show that those chemicals are not detectable in the authorised gel (NUSIL), but are detectable in both PIP1 and PIP2 unauthorised gels to varying levels. Assessment by TGA is showing different characteristics for the unauthorised and authorised gels. These tests are on-going.
Presence of metals
Samples of unused PIP breast implants have been being screened for the presence of metals using inductively coupled plasma mass spectrometry (ICP-MS). No metals have been identified at a level that was considered to be of concern.
Presence of D4, D5 and D6 siloxanes
AFSSAPS noted that some batches of unauthorised gels contained higher amounts of small silicone molecules (called low molecular weight siloxanes) than the authorised gel. Thus, the TGA is testing the gels to determine the presence of D4, D5 and D6 siloxanes. Test results from GC-MS analyses indicate D4 is present in the gels of PIP breast implants at between 0 and 261ppm, with a median of 136ppm. D5 is present between 0-710ppm, with a median of 434ppm. D5 is present between 0 and 1005, with a median of 470ppm. There does not seem to be any relationship between the year of manufacture of the gel and the presence of D4, D5 and D6 siloxanes. These values could change with the testing of further samples.
Information provided by the suppliers of the raw materials, which were used to produce the gel used in PIP breast implants, together with more recent detailed information provided to the TGA by AFSSAPS, does suggest that the TGA findings are a reasonable estimate of the content of these siloxanes.
The TGA has increased the number of samples of PIP breast implants tested for shell integrity by measuring the tensile elongation of a further 7 samples to the original 8 samples that were tested in 2010. All tensile elongation results for the 15 samples now tested meet the requirements of the standard (ISO 14607:2007 Annex B Section 1.2) - the elongation at break of the shell specimen must exceed 450% compared to the original length of the specimen.
To date, samples of gels that have been tested for cohesion have met the requirements of the standard. The TGA has observed that most filler gels from either unused or explanted PIP breast implants appear to be firm. However, the TGA has noticed that the occasional gel appears relatively less firm. The significance of this observation is being further investigated.
|Model||Lot No.||Expiry||Thickness (mm)||Force (N)||Elongation (%) |
Requirement is >450%
|Gel Cohesion (mm) |
Requirement is <30mm
Investigation of explanted breast implants
The TGA is investigating breast implants that have been explanted from patients to augment the information that has been provided to the TGA by surgeons.
Generally, the gels from explants investigated to date have been firm and strongly cohesive, although the TGA has observed gels that are less firm. To date, the ruptured explants received by the TGA are associated with a 'milky fluid'. An aliquot of the milky fluid was chemically fingerprinting using FTIR and this indicated that the milky fluid was predominantly water with polydimethylsiloxane (silicone).