21 CFR part 11 at a glance

21 CFR part 11 at a glance

21 CFR part 11 was published in August 20,1997,  it applies to ‘ Electronic records and Electronic Signatures’. In general the regulation requires organizations to have 3 levels of controls in place. They are 

·       Administrative controls

·       Procedural controls

·       Technical Controls

21 CFR part 11 is divided in to 3 sub parts.

Subpart A--General Provisions
   Scope.
   Implementation.
   Definitions.
Subpart B--Electronic Records
   Controls for closed systems.
   Controls for open systems.
   Signature manifestations.
   Signature/record linking.
Subpart C--Electronic Signatures
   General requirements.
   Electronic signature components and controls.
   Controls for identification codes/passwords.

  Few important things about 21 CFR part 11 are

1.    Part 11 mandates that closed and open computer systems must have controls to protect data and keep it confidential. System access to be limited to authorized individuals.

2.  All computerized data storage systems containing information that is reported to the FDA or used to make Quality decisions must be Part 11

3.  Validation of the computer systems must be performed to ensure accuracy, reliability, consistent intended performance and the ability to discern invalid or altered   records. This means that the system owner maintains validation documentation including testing protocols and requirement specifications.

4.  All data entered into the system must be retrievable without changes being made.

5.  Procedural controls must be maintained to ensure records are not corrupted.

6.  A system owner must show that s/he is aware of who is accessing the data at all times.

7.  System owners must keep an audit trail. This is time stamped log, which is internal to the system and designed to record all changes related to system data like creation, modification, deletion etc.

8.  Regular device checks must be made. This means that checks must be made to ensure that operational instructions and all system data inputs are accurate.

9.  All system users must be specifically trained to use 21 CFR 11 compliant programs.

10.               When using electronic signatures, all users must acknowledge awareness of their responsibility for any data entered or edited within the system.

 

Gluten in Pharmaceutical products

Gluten in  Pharmaceutical products

Gluten is a protein found in wheat, barley and rye. Celiac disease (coeliac disease/celiac spur) is an auto immune disease of the digestive tract that affects about 3 million people in united states. When patients with celiac disease ingest gluten, an immunologically mediated inflammatory response occurs that damages the mucosa of the intestine resulting in maldigestion and malabsorption, abdominal pain, diarrhoea, constipation, vomiting and other problems. The treatment for celiac disease is adherence to a gluten free diet.

It is recognized that pharmaceutical products may contain traces of gluten, which will cause acute illness in celiac patients. Potential source of gluten contamination in pharmaceuticals come primarily from excipients (i.e Wheat starch is occasionally used as an excipient  in the formulation of medicinal tablets and capsules in variety of functions, as a diluents, a disintegrant, a glidant or as a binder). However  there is currently no regulatory guidance in place on the acceptable levels of gluten in medicinal products.

Despite few pharmaceuticals are labelled as gluten free, the great majority of drug manufactures do not specify on the product label information regarding gluten content. A great concern comes from the generic drugs which may not contain the same excipients as the brand product.

Declaration of gluten in pharmaceuticals is very important task required for display the gluten status of the product, as the absence of gluten remains the only treatment for celiac patients.

ETO – Sterilization process for pharmaceutical products

ETO – Sterilization process for pharmaceutical products

Ethylene oxide (ETO) is a colorless liquid (it is liquid at temperatures below 10.8^oC). ETO has been widely used as a low-temperature sterilant. It has high penetrating power and passes through and sterilizes large packages of materials including plastics. It is most commonly used to sterilize medical and pharmaceutical products that cannot support conventional high temperature steam sterilization or materials that may be deteriorated by radiation sterilization.

Mode of action – The microbicidal activity of ETO is considered to be the result of alkylation of protein, DNA, and RNA. Alkylation, or the replacement of a hydrogen atom with an alkyl group, within cells prevents normal cellular metabolism and replication.

ETO gas boiling point is 10.73 ºC at atmospheric pressure and is highly explosive when pure. Normally the ETO used for gas sterilization is mixed with diluents such as carbon dioxide or nitrogen in different proportions from 10 % ETO to 90 % ETO to eliminate explosive tendency.

Critical process parameters – Effective control of ethylene oxide concentration, temperature humidity and exposure time .

Hazards of ETO

ETO gas is highly reactive, explosive, carcinogenic and mutagenic

In addition to eye pain and sore throat, exposure to ETO can cause difficult breathing and blurred vision.

Exposure can also cause dizziness, nausea, headache, convulsions and can result in vomiting and coughing.

ETO is a carcinogen that may cause leukemia and other cancers

ETO is also linked to spontaneous abortion, genetic damage, nerve damage, pheripheral paralysis, muscle weakness.

In liquid form ETO can cause severe skin irritation upon prolonged or confined contact.

Critical process parameters for ETO sterilization – Effective control of ethylene oxide concentration, temperature and moisture.

ETO Processing steps

1. Environmental Preconditioning
Most of the EO sterilization processes starts with conditioning of the products to be sterilized in the sterilization chamber or a separate room. Preconditioning is usually performed in a room which has been specially designed to heat and humidify the products to a stable internal temperature and moisture content prior to entering the chamber. This will assure that the sterilization process is reproducible regardless of external influences such as varying climatic conditions.

• Once preconditioning is complete, the products are placed in a heated chamber which has been designed to withstand the extreme pressures realized when delivering the sterilization process.

2. Initial Evacuation
To safely deliver the 100% ethylene oxide process, at least 97 percent of the air must be removed from the chamber. Two most common methods of accomplishing this requirement are (1) pulling a deep vacuum, or (2) performing a series of partial vacuums followed by a series of nitrogen injections. This combination, when performed using an adequate number of repetitions, will purge (remove) the air, thus allowing the process to be performed safely.

3. Humidification
During the previous preconditioning step, heat and moisture were added to the product to a predetermined or stable condition. When the initial evacuation phase of the process is performed, the product can lose a significant amount of moisture. This moisture must be replaced prior to introducing the ethylene oxide. This is accomplished by adding humidity in the form of steam injections. The amount of steam required is calculated to yield a predetermined relative humidity. After the addition of steam, the product is allowed to dwell or soak for the amount of time required to replace the moisture lost from the evacuation phase.

4. Gas Injections and Gas Dwell
After the humidification phase, liquid ethylene oxide is first heated into a gaseous phase, then injected into the chamber. The amount of gas or gas concentration is dependent on two primary factors which are addressed during cycle design.

The most important factor is to assure that the minimum gas concentration required to achieve sterility within the product is attained. This minimum  concentration must be balanced against the second factor, which is the maximum amount of gas that can be injected before difficulties arise due to high levels of post-sterilization EO residuals.

After the gas has been injected, the exposure phase of the process is performed. This is the phase in which the product is exposed to heat, relative humidity, and gas for a predetermined amount of time. As a rule of the thumb, the more difficult the product is to sterilize, the longer the exposure time. The amount of exposure time is determined by the process design scientist, after careful analysis of the product, load configuration, and desired level of sterility. Preliminary laboratory experiments may be needed prior to validation execution.

5. Post exposure Gas Purge and Air Inbleed
After the exposure phase of the process, all gas must be removed from the chamber until the levels of EO fall below the flammable limit for the gas (3 percent or 30,000 ppm). This is accomplished by performing a series of post-vacuums, each followed with a nitrogen backfill (wash).

A maximum working pressure for the washes is selected by the process design scientist to assure that the products, which may have been softened during the exposure phase of the process, will not be damaged. An ample number of washes is performed to reduce product residues and facilitate safe handling of the product after processing.

6. Aeration
To reduce the amount of residence time in the vessel, products after sterilization are usually placed in a heated room for additional removal of the residual gases. The rooms are maintained at elevated temperatures and the out gassed residues are continuously removed from the room and scrubbed. The aeration rooms help contain any airborne EO and continually reduce the in-product residues.

 

ETO Processing steps

Preconditioning/conditioning - Precondition to a specified RH and temperature

Sterilization cycle - Exposure to ETO gas

Aeration - Dissipation of remaining gases

Typical ETO treatment conditions:

Temperature between 30°C and 60°C

Relative humidity above 30%

Gas concentration between 200 and 1000 mg/L

Exposure time of 2 to 10 hours

ETO validation

The validation of EO sterilization processes, which includes physical and microbiological performance qualification, is described in detail in ISO 11135 and European Norm (EN)  550.Following tests  to be performed as a part validation.

1.    Bioburden measurement

2.   EO residual measurement

3.   One fractional cycle

4.   3 Half cycle

5.   One full cycle

Half Cycle Qualification

This method involves determination of the minimum time of exposure to Ethylene oxide, with all other process parameters except time remain constant, at which there are no survivors. Two further experiments should be performed to confirm the minimum time. All three trials should show no growth from the biological indicators. The specified exposure time should be at least double this minimum time. In each cycle biological indicators containing about 10⁶ viable spores of Bacillus atrophaeus complying with AAMI/ISO-11138 shall be used. A minimum of 3 successful half – cycle tests shall be performed for  the load configuration to show that the process and subsequent results are repeatable. The half cycle will demonstrate that the selected minimum time of exposure to ETO during the sterilization process will repeatedly achieve 100%  kill of the BI located with the load. This time then will be double to produce the exposure time for routine processing of the product load.

The biological indicators shall be retrieved after the sterilization cycles and incubated at 30 – 35⁰ celsius for 48 hours. 2 unprocessed biological indicators shall be incubated as positive controls. Sterility testing shall be carried out after each half cycle. The samples should pass the sterility test.

Full Cycle

One full cycle of twice the exposure time of half cycle shall be conducted to confirm the exposure period. The biological indicators shall be retrieved after the sterilization cycles and incubated at 30 – 35⁰ celsius for 48 hours. The samples should pass the sterility test.

Fractional Cycle

One 1/6^th cycle shall be performed to demonstrate that BI has resistance greater than  or equal to the natural product resistance. The cycle is intended to achieve partial positive and partial negative results.

Advantages of ETO sterilization are: Low temperature High efficiency – destroys microorganisms including resistant spores Large sterilizing volume/ chamber capacity Non corrosive to: plastic, metal and rubber materials Disadvantages are: Excessively Long cycle Safety concerns - carcinogenic to humans Toxicity issues - toxic residues on surgical instruments and tubing Not recommended for flexible scope ETO is flammable Requires special room conditions, safety equipment and separate ventilation system Relatively high annual costs for maintenance and consumables

Facts to be remembered about ETO sterilization

ETO gas is highly reactive, explosive, carcinogenic and mutagenic

ETO reacts with cellular proteins and nucleic acids

B. atrophaeus is the recommended biological indicator  ETO sterilization

Process variables for ETO sterilization include pressure, ethylene oxide concentration, temperature, humidity and exposure time.

Due to flammability ETO is often diluted with fluorocarbon gases or carbon dioxide.

ETO sterilization is the least aggressive form of the sterilization, often resulting in no change in properties or appearance

ETO sterilization is conducted at temperatures in the 50 -600C range.

ETO is absorbed by many materials. For this reason, following sterilization the item must undergo aeration to remove residual ETO.

As a part of ETO validation a microbial challenge must be performed to demonstrate adequacy of the processes to achieve the desired sterility assurance level.

In view of the known positive potential of ethylene oxide for genotoxic carcinogenicity, it is recommended that use is acceptable only when pharmaceutically absolutely necessary, and then residual ethylene oxide in the product should not exceed a limit of 1 ppm (EMEA guideline)

All BI from the half and full cycle should show no growth on incubation.

The BI used for positive control and some BIs in the fractional cycle should show positive growth.