21 CFR Part 211 compliance requires the manager of any regulatory controlled manufacturing company to manufacture all medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this 21 CFR Part 211 compliance is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers and by the distributors.
To achieve 21 CFR Part 211 compliance there must be a comprehensively designed and correctly implemented system of Quality
Assurance Incorporating Good
Manufacturing Practice, and thus Quality
Control and Quality
Risk Management. It should be fully documented and its effectiveness monitored.
All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the manager of the manufacturing authorization and for the authorized person(s). The basic concepts of Quality Assurance, Good Manufacturing Practice as legislated for in 21 CFR Part 211, Quality Control and Quality Risk Management are inter-related. They are described here in order to emphasis their relationships and their fundamental importance to the production and control of medicinal products.
The basic principles of quality assurance; as published in 21 CFR Part 211, have as their goal the production of articles that are fit for their intended use. These principles may be stated as follows:
safety, and effectiveness must be designed and built into the product
Quality cannot be inspected or tested into the finished product:
Quality Assurance; as detailed in 21 CFR Part 211, is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum and total of the organized arrangements made with the objective of ensuring that medicinal products are compliant with the requirements detailed in 21 CFR Part 211. Quality Assurance therefore incorporates Good Manufacturing Practice (GMP) plus other factors outside the scope of this Guide.
The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that:
Specifications describe in detail the 21 CFR Part 211
requirements, with which the products or materials used or obtained
during manufacture have to conform. They serve as a basis for quality
evaluation. Manufacturing Formula, Processing and Packaging Instructions
state all the starting materials used and lay down all processing and
Procedures give directions for performing certain operations e.g.
cleaning, clothing, environmental control, sampling, testing, equipment
operations, as detailed in 21 CFR Part 211.
Records provide a history of each batch of product, including its
distribution, and also of all other relevant circumstances pertinent for
quality of the final product.
Documents should be designed, prepared, reviewed and
distributed with care. They should comply
with the relevant parts of the manufacturing and marketing authorization dossiers as detailed in 21 CFR Part 211.
Documents should be approved, signed and dated by appropriate and authorized persons.
In accordance with 21 CFR Part 211 documents should have unambiguous
nature and purpose should be clearly stated. They should be laid out in
an orderly fashion and be easy to check. Reproduced documents should be
clear and legible. The reproduction of working documents from master
documents must not
allow any error to be introduced through the reproduction
Documents should be regularly reviewed
and kept up-to-date. When a document has been revised, systems should be
operated to prevent inadvertent use of superseded documents. As
detailed in Part 11 and 21 CFR Part
Documents should not be hand-written; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.
Any alteration made to the entry on a document should
be signed and dated; as per requirements in 21 CFR Part 211, the alteration
should permit the reading of the original information. Where appropriate, the
reason for the alteration should be recorded.
The records should be made or completed at the time each action is taken
and in such a way that all significant activities concerning the manufacture of
medicinal products are traceable. They should be retained for at least one year
after the expiry date of the finished product.
Data; in accordance with 21 CFR Part 211 legislation may be recorded by electronic data processing
systems, photographic or other reliable means, but detailed procedures relating
to the system in use should be available and the accuracy of the records should
be checked. If documentation is handled by electronic data processing methods,
only authorized persons should be able to enter or modify data in the computer
and there should be a record of changes and deletions; access should be
restricted by passwords or other means and the result of entry of critical data
should be independently checked. Batch records electronically stored should be
protected by back-up transfer on magnetic tape, microfilm, paper or other means.
It is particularly important that the data made available by 21 CFR Part 211 is readily available throughout the
period of retention.
When goods or services are purchase by a cGMP approved organization from a none cGMP approved vendor; it is a legal requirement that the would-be purchaser audits the supplier to establish the scope of any work required to render the item or process cGMP compliant
This elevates the Vendor Audit (VA) Document to a “Must be in Place” status. So, your list of pre validation doc's must include: (VA) + (FAT) + (SAT)
These are mandatory & available as a package;
Why does something as simple as a spreadsheet figure in so many regulatory citations? Good question; at times a difficult one to answer. When you ask a group of compliance personnel the same question you will be informed that Excel cannot be validated because it does not seal the original copy (of the spreadsheet), allows the original to be modified and has an audit trail that can be disabled. All true, but none of these problems interfere with your ability to validate that the spreadsheet is fit for purpose; as is the requirement in 21 CFR Part 211. They only preclude you from using the spread sheet as a compliant repository for any data that has to be store in compliance with 21 CFR Part 11. If the spreadsheet is signed off by the user, their supervisor and QA, it becomes acceptable data stored in hard-copy, and Part 11 does not apply.
This matrix gives a clear and concise overview of all spreadsheets in company use. It indicates the current validation documentation status and the individual spreadsheet issue levels. This matrix is a regulatory required document; as per 21 CFR Part 211.
This Computer Vendor Audit document should be customized using the find and replace word feature. The document can then be re-focused to reflect your project priorities. The fifteen chapters all contain 10 questions applicable to 21 CFR Part 211. The total scored is then weighted to reflect your priorities. By assessing the importance of each of the chapter subjects in your project, the weighting is altered taking points from one and adding to others. For example in a recent audit, after weighting, order of priorities became; delivery number one, validation number two, and price trailing at number nine. The document has been used to audit major computer equipment suppliers including two of the major DCS system suppliers in the petro/pharma/bio world.
Use it wisely it is a very searching audit tool, and completely removes the possibility of suggestions that personal biases and opinions influenced the final audit decision. When you audit with this document; they know they have been audited for compliance with 21 CFR Part 211, and you have the documented information to advise your company or client on the suitability of the vendor.</div>
The Performance Qualification is the last of the qualifying tests that equipment and processes are subjected to, prior to the actual first product run. It maybe that there are some steps in the process that can only be verified by actually running them (quick freezing and sublimation, to mention only two) or it some-times is the fact that the product is a very expensive product, and can not be wasted. So no one wants to run the process with product, until they are completely certain there will be minimal waste; 21 CFR Part 211 refers.