Infusion fluids are sterile solutions in water, intended for injection by slow drip directly into a vein. The production of infusion fluids on an industrial scale is a straightforward process. The prime requirement being the preparation of as clean as possible a fluid.
What happens when this prime requirement is violated is illustrated by the “Clothier Report”. This report was commissionned by the Secretary of State for Social Services of the United Kingdom in March of 1972. The report is named after it’s chairman; C. M. Clothier.
At the time of the incident the method of producing clean (clean in the sense of containing very few bacteria) fluids was well known.
The fluids are filled into containers and sterilized by heat.
The standard procedure is to maintain the fluid at 115 degrees Celsius for 30 minutes, which is considered sufficient to kill all vegetative forms of bacteria. The process of steriliziation is carried out in an autoclave. Within these autoclaves closed containers of infusion fluid are exposed to steam under pressure. Increased pressure is needed to achieve, with steam, temperatures in excess of 100 degrees Celsius.
To secure satisfactory sterilization autoclaves must be operated so that the contents of all containers in a load are held at the correct temperature for the correct time. The temperature of the steam entering the autoclave can be different from the temperature of the load: the temperature of the load and the time for which it is held are what matters.
There is a lag of time between the first admission of steam and the attainment of the correct temperature by the entire load. During this lag, the air is displaced downwards and out of the autoclave. Until this displacement is complete, the resulting air-steam mixture within the autoclave has a lower temperature than that of the steam.
Timing of the sterilization period must not begin until the lad period has been completed. The lad period is the period until all air has been displaced and the autoclave contains only steam and the load to be sterilized.
To ensure sterilization, the temperature inside the autoclave must be monitored. This was commonly done by observing the temperature of the steam in the autoclave, not the temperature of the load. When this method is used, it is essential for the temperature recorder to show the temperature of the steam in the coolest part of the autoclave.
In most autoclaves, this is the condensate drain. This is the location where the temperature recorder sensor should be inserted. Regular checks should be done to verify the relationship between the recorded temperature in the drain and the load temperature.
Under perfect conditions the two temperatures will be the same. Any significant differences will indicate a fault.
On April 6, 1972 a batch of 5% dextrose influsion fluid (Dextrose Injection BP) was produced in the factory of Evans Medical without adequate steriliziation due to under-processing within an autoclave. As a result, about one third of the bottles contained live bacteria which escaped detection at the factory. Notwithstanding a record of defective processing the batch was released for sale.
During the interval between production, sale and use, the remaining bacteria multiplied, producing a dangerous degree of contamination,
The batch of contaminated product was distributed to wholesalers, some of it reached the Plymouth General Hospital on 24 February 1972 and 01 March 1972. The delivery included both sterile and contaminated bottles in the proportion of approximately 2:1. Some of the contaminated bottles were used in the treatment of patients, despite all normal precautions by the hospital staff.
As a result of a succession of untoward reactions in patients at the hospital between March 1 and March 3 1972, bottles of the batch came under suspicion and were subjected to bacteriological examination. On the 4th of March, it was confirmed that the bottles were contaminated.
The contaminated batch in question; D1992/C was produced by the Transfusion Unit at Evans Medical which consisted of two sections;
The autoclaving section contained six autoclaves, each fitted with a recording thermometer with it’s sensor located in the condensate drain. Each autoclave is also fitted with a pressure gauge and dial thermometer, both sensing from the top of the autoclave, at -or near- the steam inlet pipe.
Evidence was given to the investigative committee that the dial thermometers were used in an earlier method of operation. They were not intended to be used in connection with process current since about 1966 – the Evans Medical SOP’s on the autoclaving section produced in 1967 make no reference to them.
The method of sterilization employed by Evans Medical follows that described in Production of Infusion Fluids above; the Evans Medical operating instructions for autoclaves are reproduced as an excerpt below this paragraph.
From the evidence of the autoclave operating staff, Mr. Anthony Drummond, an autoclave operator, Mr. Peter Murphy, the chargehand, and Mr. George Sefton, the supervisor, it seems clear that the autoclaving plant had been giving trouble for some time before April 1971. This trouble was evidenced by the temperature recorders either showing a temperature below 240° F (commonly 230° F, or slightly more), or failing to indicate any rise in temperature.
The evidence of Mr. Drummond was that the temperature recorder for autoclave number 4 was the most troublesome and that the fault it exhibited was that on occasions it did not record in the sense that the pen did not move from the baseline.
On each occasion he reported this to one of his supervisors who would call in either the instrument technician or the engineer. After inspection autoclaving would proceed. Mr. Drummond’s recollection was that generally the recorder would work again after this attention.
Mr. Murphy gave evidence that autoclave number 6 hadgiven trouble to the extent that on occasions the temperature recorder indicated temperatures below 240° F, as low as 230° F, at the beginning of a cycle.
When this happened the practice was to check that the steam trap was operating and that the pressure was correct, and if they were, to continue the sterilizing cycle.
It should be mentioned that Mr. Murphy gave evidence that he was not aware of any occasions on which temperature recorders had shown no rise in temperature above the baseline.
The Committee believes that he was mistaken in his recollection on this point; the evidence of all others in the ‘Iransfusion Unit concerned with the operation of autoclaves was that there were a number of occasions on which the temperature recorder of number 4 autoclave did not indicate any rise in temperature above the baseline.
Mr. Sefton gave evidence that from about December 1970 trouble had been experienced with the temperature recorders ofautoclaves numbers 4, 5 and 6, on some occasions the recorders showing a slightly low temperature, on others no rise in temperature at all.
On these occasions Mr. Coles, the engineer and Mr. Carter, the instrument technician would be called, and on most of the occasions on which he came Mr. Carter would advise thatthe recorder was broken. Mr. Sefton would then satisfy himself that the autoclave was working properly, by checking that the steam drain and steam trap were working correctly, and continue the sterilizing cycle mainly in reliance on the correct pressure having been achieved.
Mr. Brian Devonport, the manager of the Transfusion Unit, gave evidence that by December 1970 the temperature recorders had given trouble on a number of occasions.
About December 1970, after discussion with Mr. Carter, the instrument technician,
Mr. Devonport made a late manuscript addition to the capital estimates for the Transfusion Unit for the year 1971 -7 2, in effect requesting the replacement of all six temperature recorders, but for one reason or another this request was not followed up.
This point will be referred to again later in this article.
It should be mentioned here that Mr. Carter ‘s evidence was that he could not recollect any occasion in the period from the autumn of 1970 until he received a request on 6 April 1971 on which he had been called to the Transfusion Unit to look at the recorders.
The Committee believes his recollection is at fault on this point, and is satisfied that the temperature recorders appeared to the staff of the Transfusion Unit to need fairly frequent attention.
Records of maintenance of the autoclaves were produced to the Committee.
These showed an initial burst of activity after the overhaul of maintenance records in 196 7, but the system rapidly fell into disuse. By the autumn of 1969 virtually no entries were being made on the records, and as indication of the condition of the plant the records were virtually useless.
It should be mentioned here that a check of temperature record charts carried out after this incident of contamination had come to light indicated that on some 70 occasions over the period between May 1970 and September 1971 sub-batches of products had been produced for which the temperature recorder chart showed an inadequate cycle, generally no rise in temperature, or a temperature below the necessary 240 ° F.
It is not now possible to say whether sterilization was inadequate on these occasions but it seems probable that this was the case for at least some of the sub-batches.
From the Committee’s point of view in relation to its terms of reference, the importance of these records is that they confirm that an unauthorized procedure for operating autoclaves had become established.
On 6 April 1971 a batch of 5% dextrose infusion fluid numbered D1192, just over 4 ,000 bottles in all, was processed in the autoclaves of the Transfusion Unit.
As was the custom, the batch was divided into six sub-batches and each given a suffix A to F according to the autoclave in which it was to be processed. The order of starting up the autoclaves was 6, 5, 4 etc., and sub-batch C 6 was placed in autoclave number 4.
The number of bottles constituting the sub-batch was 612; these were loaded into two cages, each of which had three levels.
On this day both the supervisor of the solution-making, filling and autoclaving section of the Transfusion Unit, Mr. Sefton, and the chargehand, Mr. Murphy, were absent for different reasons. Thus Mr. Devonport, the departmental manager, was singlehanded so far as supervision of the work of this section was concerned, including the operation of the autoclaves. The autoclave operator at work on this day was Mr. Drummond.
Mr. Drummond’s evidence was that on this day he started the sequence of operations necessary on autoclave number 4, but found that after the admission of steam to the autoclave had begun, the temperature recorder did not indicate the expected risein temperature.
Mr. Drummond reported this to Mr. Devonport, and it seems clear that both assumed that this was another instance of recorder failure.
With hindsight it is possible to say that there is a probability amounting almost to a certainty that the recorder was functioning and correctly indicating no rise in temperature in the condensate drain. However, autoclaving was continued according to the procedure which had become established in reliance on the dial thermometer indicating a temperature of 240° F., and the pressure gauge indicating a pressure of 10 lb. per square inch above atmospheric pressure, ignoring the recorder indication.
At the public hearings Counsel for Evans Medical made the point that the operating instructions laid down by Evans Medical for autoclaving had not been followed. In particular it was said that, if the instructions had been followed, processing could not have been continued, since they called for the marking of the temperature trace for the beginning of the cycle at the point where it reached 240° F.
However, other evidence given to the Committee indicated that the operating staff had found two other instructions -number 8 and number 9 -needed interpretation to produce a satisfactory result.
The positioning of the pressure gauge was such that following instruction number 8 could lead to the introduction of air to the autoclave because it indicated a positive pressure ( above atmospheric) when a partial vacuum still existed. Thus it became the practice to shut off the steam at intervals and then read the pressure before continuing steaming, if necessary, to ensure that there was a slight positive pressure before opening the condensate drain valve.
So far as instruction number 9 is concerned, evidence was given that it was necessary to close the condensate drain valve when the temperature had reached about 220° F., otherwise the autoclave would not reach the required 240° F.
The operating staff therefore knew that in two respects the operating instructions could not be regarded as mandatory. So far as the use of the temperature recorder was concerned, the staff had available a dial thermometer which had been observed to indicate the same temperature as the recording themometer when all was functioning correctly.
In fact Mr. Drummond said in evidence that he had been told to use the dial thermometer in the event of the recorder not working. It is true that the operating instructions did not say that this dial thermometer could be used; it is also true that the instructions did not say that the dial thermometer must not be used. The Committee finds it difficult to criticize the operating staff for using the dial thermometer in their endeavours to continue production, when there was no clear instruction to the contrary.
Processing of sub-batch D1192C therefore continued making use of the dial thermometer and pressure gauge, and so far as could be recalled by the staff concerned all proceeded normally.
In reality all was far from right; it was later shown that of the bottles recovered from sub-batch D1192C approximately one third were contaminated and on this evidence could be assumed not to have been sterilized. The remainder were sterile.
Various theories were advanced as to how this came about, for example, that air could have been admitted in error during the processing, or that water could have been present to a considerable depth in the bottom of the autoclave. But the only theory fully consistent with the established facts was that a layer of air was present in the bottom of the autoclave surrounding the lowest of the three layers of bottles, thermally insulating them from the steam in the upper part of the autoclave. This is illustrated in the image below:
After the discovery of the contamination in March 1972 , Inspectors of the Department of Health and Social Security conducted an investigation of the Transfusion Unit at Evans Medical, and one of them, Mr. George Wilkinson, carried out a series of experiments with the autoclaves in an endeavour to reproduce conditions in which bacteria could survive in bottles at the bottom of the autoclave and yet not in the remainder, during the operation of a sterilizing cycle.
This result was reproduced only when two conditions were met simultaneously:
In these conditions the chart produced by the recording thermometer showed a marked similarity to that produced in evidence relating to sub-batch D1192C; the bottles in the upper part of the autoclave reached the correct temperature (240° F.) while bottles in the lowest layer did not exceed a temperature of 118° F. during the cycle.
The loading of the bottles in the autoclave in three layers, the experiments conducted by Mr. Wilkinson, and the results of the laboratory examinations, taken together, are sufficient to convince the Committee that about one-third of sub-batch D1192C failed to reach sterilizing temperature and that this failure was caused by a retention of air within the autoclave throughout the sterilizing cycle.
The experiments of Mr. Wilkinson showed that to reproduce the result of failing to sterilize in the bottom layer of the autoclave, the drain from the sterilizing chamber had to be blocked and no use made of vacuum partially to remove air at the start of processing.
Evidence was given that broken glass or other debris commonly collects in the bottom of autoclaves and that on the occasion of Mr. Wilkinson’s visit in March 1972, he found a considerable amount of such debris in autoclave number 4, sufficient to indicate to him that cleaning was not then being carried out often enough.
The maintenance records of the autoclaving plant are inadequate to indicate whether or not debris was regularly cleared from autoclaves, but copies of Works Orders (requests for maintenance or repair work) produced to the Committee in relation to the period surrounding 6 April 1971 for autoclave number 4 give a strong indication that there was trouble, in all probability connected with blockages, at that time. For example, on 1 April there was a request for the trap to be checked -this would be the steam trap at the bottom of the autoclave -on 5 April a request to check the instruments, and on 7 April a request to provide a replacement probe “before removing the present defective one for service” ( this is the sensor for the recording thermometer).
There can be no certainty now that vacuum was used, as required by the operating instructions, for the processing of subbatch D1192C -the autoclave operator’s recollection was that all proceeded normally.
But in the absence of any other explanation, failure to reach sterilization temperature of part of the sub-batch may well have been caused by failure to use vacuum properly or at all.
It has been mentioned earlier in this report that the standard requirement for sterilization is that the fluid must be held at 240° F. for a period of 30 minutes. The operating instructions of Evans Medical provided for holding the necessary temperature for 40 minutes to provide a margin for safety.
There is some evidence to show that the processing cycle for sub-batch D1192C was less than 40 minutes, but the evidence is insufficient to establish whether or not the minimum of 30 minutes at the necessary temperature was achieved for bottles in the two upper layers of the autoclave. However, in the light of the fact that two-thirds of the bottles of the sub-batch recovered were shown by laboratory examination to be sterile, the Committee concluded that a satisfactory cycle must have been achieved for the two upper-layers.
In 1966 infusion fluids manufactured in the Transfusion Unit of Evans Medical were found to be contaminated. The cause of that contamination was not connected in any way with the incident which was the subject of this Inquiry, and the Committee considered that it was no part of its task to investigate the 1966 incident. The relevance of the events of 1966 to the present Inquiry is that the earlier incident led to investigation of the Transfusion Unit by Staff of Evans Medical and also by Inspectors of the (then) Ministry of Health. These investigations resulted in a radical reorganisation of the Transfusion Unit, the development of the current autoclave operating instructions, and a number of recommendations by the Ministry Inspectors.
In addition, and most importantly, an understanding was reached between the management of Evans Medical and Inspectors of the Ministry of Health as to the role of quality control in the management of the production of infusion fluids.
There is no doubt that most of the recommendations by the Ministry Inspectors were acted on. One which did not receive the attention it deserved was that frequent checks should be made to determine the temperature within the bottles of the load in the autoclave and the relationship between these temperatures and the condensate drain temperature. Checks were made in 1966 and 1967 to prove the operating instructions, but very few checks were made after 1967. From what emerged in evidence at the Inquiry it seemed likely that the equipment had been allowed to deteriorate to an extent which would preclude its use for such tests.
Evidence was given to the Committee by Inspectors of the Department of Health and Social Security that an oral recommendation was made in 1966 that the dial thermometers should be moved so as to sense from the autoclave drains, but witnesses from Evans Medical could not recall that such a recommendation was made.
There is no doubt that the Ministry Inspectors were left with the impression that their recommendation that the quality control department should be encouraged to assume full powers on appropriate matters relating to the Transfusion Unit had been accepted and put into operation.
During the hearing a number of references were made to the “Orange Guide,” a booklet entitled “Guide to Good Pharmaceutical Manufacturing Practice” published by HMSO for the Government Health and Agriculture Departments in 1971.
This was produced in co-operation with industry and consists of a collection of principles of known, and accepted good practice, and detailed guidance based on these principles. One of the principles deals with quality control and indicates that in a manufacturing organisation there should be a separate department responsible for the testing of raw materials, intermediate and final products, and their release for further processing or for sale, and also for the approval of methods and their periodic review.
In evidence, Dr. Smith, the managing director of Evans Medical, agreed that the company had available a draft for the “Orange Guide” in 1970 and that he accepted and agreed with the guidance it contained. F urther, he had given instructions to the company’s chief analyst (who may be regarded as the head of “Quality Control” at Evans Medical) to do whatever was necessary to implement the Guide. In fact, as will be shown in the following section, the management of Evans Medical departed from the known principle of quality control in regard to the production of infusion fluids in vital respects even with knowledge of the recommendations of the Ministry Inspectors that had been made following the 1966 incident.
The practice of Evans Medical for infusion fluids was followed in relation to the clearance for sale of sub-batch D1192C. Sample bottles from the sub-batch were taken by laboratory staff for chemical testing and by production staff for despatch to the biological control laboratory (part of the Chief Analyst’s domain) for sterility and pyrogen tests.
Information indicating that the test results were satisfactory was sent to Mr. Devonport, the Transfusion Unit manager, and he signed the release for sale. Each bottle of the sub-batch was examined by trained operators before being sent to the finished goods store. The temperature recorder chart relating to the sub-batch was filed by Mr. Devonport.
This procedure was faulty in several respects. The principal fault lay in the practice of placing the decision to release a batch for sale in the hands of production staff instead of quality control staff, as indicated by the “Orange Guide.”
A necessary part of the information on which quality control staff would reach a decision on release would be the temperature recorder chart, and in practice this vital document did not leave the production department and was not seen by anyone outside the production department. Had the decision on batch release been in the province of quality control, it seems certain that all tests and production records (including the recorder chart) would have been examined together before the decision was reached.
The Committee considers it certain that an independent quality control examination of records of a batch for which there was no evidence of a satisfactory sterilizing cycle would have resulted in a decision not to release the batch for sale.
A second serious fault lay in the selection of samples for sterility and pyrogen tests. In contrast to the samples for chemical tests, these samples were selected by production staff.
It is not clear whether instructions as to the manner of sampling had ever been given to the production staff, but at all events there were no written instructions. In the absence of firm direction from quality control, samples were in practice selected by production staff only from the top layer in each cage, no doubt because this was the easiest course.
It is the Committee’s opinion that in sub-batch D1192C bottles in the two upper layers of the cages were sterile, and those in the lowest layer were not sterile.
It cannot now be established whether a sampling technique which would draw samples from the lowest layer in each cage would have revealed the failure of sterilization in part of sub-batch D1192C, but it may be said with confidence that the method of sampling used by production staff made it impossible for the sterility tests to detect such a failure affecting, as the Committee judges that it did, only the lowest layer of bottles.
Evidence given to the Committee revealed a number of shortcomings in management in Evans Medical at various levels and in different quarters. It could be said of any one of these shortcomings that it was a potential cause of the disaster but in the Committee’s view they were not causatively of equal importance or equally deserving of condemnation.
There was clearly a failure by the autoclave operator to follow the operating instructions. The Committee considers that no real responsibility lies with him; it was for his supervisors to check that the operating instructions were carried out.
Mr. Devonport, the manager of the Transfusion Unit, must take some share of the responsibility for the manufacture of the faulty batch.
He is a qualified pharmacist and his training for this qualification covered the theory of sterilization by means of autoclaves.
In spite of his theoretical knowledge he established or allowed to become established a wholly inadequate procedure for operating the autoclaves under his command.
He failed to take the obvious managerial step of checking on the actions of his operating staff, tending to rely too much on their supervisor, Mr. Sefton.
It is clear that he believed the equipment to be faulty and that he brought this to the notice of the engineering department and of his superior, Mr. John Smart, the production manager, but the Committee considers that faced with the apparent failure of a vital part of the autoclave equipment, Mr. Devonport’s action lacked the necessary vigour.
However, it must be said that his background before joining Evans Medical did not include practical knowledge of the operation of autoclaves and that his training for the post of manager of the Transfusion Unit was wholly inadequate, apparently consisting of working alongside his predecessor for two weeks or so; Once in the post he appears to have been left to sink or swim, no effort whatever being made by his superiors to discover whether he was capable of performing the functions allotted to him, or of checking how he was discharging them.
No criticism can be made of him for his role in the selection of samples for sterility testing or in the release of sub-batches for sale; in both of these matters he did no more than continue company practice, and the responsibility must lie with quality control for its failure to establish control of these procedures.
In the Committee’s view, Mr. Smart, the production manager, must bear the major responsibility. It was he who first appointed and then transferred to the Transfusion Unit Mr. Devonport, who although a qualified pharmacist, had a background which did not include practical knowledge of the operation of autoclaves. Having appointed Mr. Devonport, Mr. Smart failed to provide him with anything approaching an adequate training. Subsequently Mr. Smart made no moves to check on Mr. Devonport’s capability or on how he was discharging his responsibilities.
The Committee are left with the impression that there was very little effective contact between Mr. Devonport and Mr. Smart, otherwise the problems which Mr. Devonport was experiencing would have come out and the use of an unauthorised procedure would have been disclosed. It is significant that not even the late addition to the capital estimates by Mr. Devonport of an item virtually requesting the replacement of all his unit’s temperature recorders prompted Mr. Smart to enquire into Mr. Devonport’s problems.
Going further up the line of command, the Committee does not consider that Mr. William Emery, the production director, or Dr. Charles Smith, the managing director, bear responsibility in any real sense for the faults in the production area. The Committee considers that in this respect they were entitled to rely on Mr. Smart.
So far as quality control is concerned, it must be said that although the company does not use the departmental title of quality control, it was accepted by the management that Mr. Charles McDonald, the chief analyst, in fact bore the responsibilities of quality control.
It was said in evidence by Dr. Smith that on receipt of the draft of the “Orange Guide” in 1970 he gave the chief analyst instructions to do his utmost to implement it. It was said that the introduction of changes necessary to bring company practice into line with that recommended in the Guide was a lengthy process and that while progress had been made throughout the company the ‘fransfusion Unit was the last in line for attention.
The Committee accepts that in any major review of this kind there must be an order of priority, but it finds it difficult to accept that there should not have been a preliminary review of procedures designed to bring out those points where the existing practice fell short of that recommended in the ” Orange Guide, ” especially in the light of previous trouble in 1966 .
Such a review would have revealed at least the major defect in release procedure in the ‘fransfusion Unit. The Committee considers that such a discovery, even as late as February 1972, would on the evidence of senior company personnel, have resulted in urgent action. The Committee considers that Mr. McDonald must be regarded as sharing some responsibility because of his failure to put in hand inquiries designed to reveal shortcomings in company practice, having had a clear mandate from his managing director.
The Committee’s principal conclusions are as follows:
There are a number of matters which the Committee recommends should be taken into account by the Medicines Commission as part of its wider inquiry.
The Matters are as follows :
The Critical Role of Proper Deviation Management
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