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1.2 Document Control SystemThis page will address various regulatory issues related to this section of the GMP Institute framework. Click below to view the issues that are relevant to you. Do the CGMP regulations specify how frequently firms must review their SOPs? Electronic Documents Part 11 Enforcement CPG Publishes Can a firm that creates batch production records in electronic form archive them as paper only? Do the CGMP regulations require firms to keep as "raw data" results from employee CGMP training tests?Reference: No. Section 211.25 of the CGMP regulations requires that persons engaged in manufacture, processing, packing, or holding of a drug product have the education, training, and experience, or any combination thereof, to perform their jobs. The regulation also requires that employees receive training, on a continuing basis, in those aspects of CGMP that are pertinent to their duties. However, the regulation is silent on training records. Note that section 211.34 requires firms to retain records of the qualifications of consultants, along with the type of service they perform. In implementing section 211.25, it should be obvious that firms need some kind of documentation regarding their employees' qualifications. Accordingly, during your inspections it would be reasonable to ask firms to show you documentation of their employee qualification and CGMP training, for your case by case assessment. Absence of training documentation combined with clear evidence that employees are not qualified to do their jobs would be appropriate observation on an FDA 483. However, absence of CGMP training test score records would not, by itself, warrant listing on the 483. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 3) September, 1999. Formulating a drug product using active ingredient overages; what can happen when there's too much of a good thing.Reference: The CGMP regulations, at Section 211.101(a) require that a batch be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient. However, this section is silent on formulating to provide more than 100 percent (i.e., overages.) Nonetheless, as discussed below, other sections of the regulations do address overages. The following case study illustrates potential problems that can result from using formulation overages when firms do not follow other CGMP provisions intended to ensure that products meet established specifications. A pharmaceutical manufacturer was routinely adding 10-16% overage (above the labeled amount) of active ingredients into a tablet formulation. The firm did this to ensure that the assay of this tablet met the label claim near the end of its expiry period. This overage did serve to extend the tablet's shelf life. However, it also caused the product to be superpotent upon release for distribution. Samples were collected and analyzed at an FDA laboratory. The laboratory results demonstrated that not only was the product superpotent, it also failed content uniformity. Moreover, CDER medical officers advised that the degree of superpotency posed a health hazard to consumers. Upon FDA's complaint, the court subsequently seized the lot that was in distribution. (The firm did not claim the goods and the court ordered the product destroyed.) This problem was not limited to the lot seized. The firm formulated all lots of this product with these overages, resulting in similar potency problems with every batch. The firm's master formula record did not justify its use of overages. The batch records demonstrated that the use of overages was inconsistent from lot to lot. (The firm has since discontinued manufacturing this product for a variety of reasons.) During your inspections, if you encounter a firm that is formulating a product at less than 100% of labeled active ingredient, the practice would be a clear CGMP violation that you should consider listing as an objectionable condition in an FDA 483. You should not automatically so list the use of overages. When you find use of overages you need to investigate the practice further to determine if, among other things, the resulting product is superpotent, or otherwise outside of its established specifications, upon its release for distribution. Section 211.165(f) of the CGMP regulations requires that drug products failing to meet established standards or specifications be rejected. It would therefore be objectionable for a firm to release for distribution a lot it had determined to be superpotent. Therefore, as part of your investigation, determine the firm's end product testing results. Note that a firm may be able to justify its decision to use overages, and the practice may not always result in product that is superpotent. It is therefore important that you review the firm's documentation, especially the master production and control record. The CGMP regulations, at section 211.186, require that the master record contain the weight or measure of each component, along with justifications for reasonable variations in the amount of components necessary for the dosage form's preparation. This section also requires that the master record contain A[A] statement concerning any calculated excess of component.@ Thus, the regulations allow for the justified use of overages in some instances. In general, firms will have determined justifiable amounts of excess components during the product's development and process validation. Contact for further information: Brian G. Nadel, HFD-325; phone 301 594-0098; e-mail: nadelb@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 7, Number 3) September, 1999. What records do the CGMPs require a firm to examine under the 211.180(e) periodic review? Must such records be stamped with a review or expiration date?Reference: Section 211.180(e) states that, "Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures." (Emphasis added) This section is intended to require firms to perform a systematic review of data relating to product specifications and manufacturing and control procedures to determine if changes are warranted. Data that indicate a need for such changes can be contained within a broad range of records. That's why the regulation is explicit in referring to records required "by this part"; part means 21 CFR part 211. The data must be in a retrievable form so firms can use the information as needed when conducting the evaluation. This does not mean that every record a firm creates to meet a part 211 requirement must be reviewed. Rather, records specified by 211.180(e)(1) and (2) must always be part of that review whereas other records would be reviewed as indications for needed change arise. The regulations give firms a great deal of latitude in exactly how they conduct periodic evaluations. However, the CGMPs establish key principles. First, the purpose of the review itself is to determine if changes in specifications or manufacturing or control procedures are needed. Second, the review both corrects and prevents product quality problems; that's why the regulations specify that reviewed batches represent those that have been both approved and rejected. [Note that although 211.180 states that "batches" and applicable associated records are to be reviewed, the preamble to the 1995 final rule that last modified this section clearly indicates that "batches" means "batch records."] In other words, indications of the need for change can be contained in records relating to conforming and non-conforming products. For example, production records for conforming lots may nonetheless indicate that a process is drifting out of control. Third, the review must be conducted at least annually. A broad CGMP principle that runs throughout the regulations is the concept of redundant checks and balances to ultimately ensure product quality. The 211.180 periodic review provides that balance with respect to change control because, in addition to having an effective change control system, reviews of records that establish product specifications or manufacturing or control procedures can help firms maintain the currency and accuracy of such things as: (1) Cross references to other documents and standards; (2) materials' specifications (e.g., ensuring they match what's in a firm's most recent NDA submission or USP monograph); (3) equipment references (e.g., too generalized a manufacturing instruction to use a "suitable mixer" where different types and sizes are at hand would need to be made specific); (4) process step sequencing; (5) process step parameters; and, (6) acceptance criteria. Especially where a firm makes significant or frequent changes, this complex matrix of interrelated instructions and specifications can make change control difficult and may result in operators using outdated or otherwise incorrect procedures or standards to make medicine. We have encountered situations where an effective periodic review could have prevented such problems. The regulations mandate that certain core records most likely to indicate a need for changes be reviewed. Included are records: (1) For each drug product covering complaints, recalls, returned or salvaged products and discrepancy/failure investigations conducted under section 211.192; and, (2) applicable to, and associated with, a representative number of batches produced over the review period. Master production records would be part of the second (batch related) grouping. Also included in that grouping would be other records that establish product specifications or manufacturing or control procedures. These records are intrinsically relevant to the review because: (1) Per CGMP, batches must be made according to those procedures and specifications; and, (2) those very procedures and specifications are what may need to be modified. Because those records may in and of themselves hold indications that changes are needed (e.g., outdated/superseded instructions), a meaningful assessment of the need for change would thus be impossible without at least a minimal review of those records. Be aware that some firms may call some records in this latter category standard operating procedures (SOPs) (e.g., how to collect an in-process sample). Although we expect that the primary indicators of the need for change reside in those records explicitly identified in 211.180(e)(1) and (2), other records may also hold indications of the need for change. Although the CGMPs don't specify those records, any included in the review need to be identified in a firm's review procedures. During your inspections, be aware of evidence indicating that a firm's review procedures may be inadequate by virtue of failing to consider relevant records that hold change indicators, especially where product defects can be attributable to a failure to make needed changes. Examples of records we would not normally expect to hold indicators of the need to change product specifications or manufacturing or control procedures include written procedures for component purchasing methods and product distribution recordkeeping. CGMPs don't require that records be affixed with review dates, nor expiration dates. Records that establish product specifications or manufacturing or control procedures (including such records that firms call SOPs) can therefore continue in effect until superseded or discontinued. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 4) December, 1998. Do the CGMP regulations specify how frequently firms must review their SOPs?References: Yes. At the referenced section, the CGMP regulations call for at least an annual evaluation of each drug product's quality standards to determine the need for changes in product specifications or manufacturing or control procedures. The rule also requires firms to establish and follow written procedures for conducting those evaluations. Such an evaluation would be incomplete if the standard operating procedures for production and process controls were themselves not reviewed. During your establishment inspections, when auditing for compliance with section 211.180, determine if the firm has established, and is following, those evaluation procedures. Also check to see if the procedures call for reviewing SOPs. Keeping SOPs current can be a challenging task when manufacturers make frequent changes or have a matrix of SOPs that cross-reference each other. Ensuring that employees are furnished with current versions of SOPs can be problematic. Therefore, during your audits, you might compare dates and version numbers of SOPs that a firm's operators use, against a master list of current SOPs. Discrepancies should be noted as objectionable conditions. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 3) September, 1998. Does the FDA Modernization Act limit FDA's OTC records inspection authority to only those records created after 2/19/98?References: No. OTC records created before 2/19/98 (the effective date of this part of the revised law) are not grandfathered. The FD&C Act now authorizes investigators to inspect records pertaining to over-the- counter, as well as prescription, drugs. The FDAMA amended 704(a)(1) by striking "prescription drugs" each place it appears and inserting "prescription drugs, nonprescription drugs intended for human use,". Investigators should not, however, routinely ask to review OTC self audit reports (a firm's own audits and inspections of its operations), although FDA reserves the right to review such records. This is consistent with CPG 7151.02, and the Congressional Joint Explanatory Statement of the Committee of Conference regarding the FDAMA. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998. Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does "objectionable" mean, anyway?Reference: Yes, the CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, be established and followed. This means that even though a drug product is not sterile, a firm must follow written procedures that proactively prevent contamination and proliferation of microorganisms that are objectionable. The meaning of "objectionable" has several facets that need to be evaluated on a case by case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Of course, most objectionable would be organisms that pose a threat of patient infection or mortality. Microorganisms may be "objectionable" by virtue of other problems. For example, microbial content that adversely affects product stability, would be objectionable. Likewise, microorganisms that react with, or potentially damage the integrity of, the container closure system (fermentation creating gaseous pressures that explode a container would be an extreme, though legitimate, example), would be objectionable. Similarly, microbial content that interferes with analytical methods, or active ingredient bioavailability, would be objectionable. For new drugs, the above considerations will likely have been addressed during the new drug review process and may result in microbial specifications for the end product. Establishing production time limits is an example of a control to prevent objectionable microorganisms. Per 21 CFR 211.111, when appropriate, time limits for the completion of each phase of production must be established and followed. Where a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to prevent microbial build up that would be objectionable. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures. Contact for further info: Brian Nadel, HFD-325, (301)594-0098: e-mail: nadelb@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 1) March, 1998. What constitutes a "representative number of batches" that must be reviewed periodically for quality standards under the CGMP regulations?Reference: The annual review established by 211.180(e) is for the purpose of "evaluating the quality drug standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures". The selection of records to be reviewed needs to consider "records required by this part" which have "data therein" and include the records specified in 211.180 (e)(1) and 211.180(e)(2). The number of batches whose associated records will be reviewed must achieve the purpose of the review. Any reasonable approach to achieve the purpose can be acceptable; the word "representative" was inserted into this regulation in January 1995 to simply confirm that every batch does not necessarily have to be included. Reviewing batches which exhibit varying manufacturing experiences is a critical element in ensuring that a "representative" selection is made. Batches showing different categories of experiences would include those that: (1) Have been approved, rejected, and recalled; (2) have unexplained discrepancies; (3) were the subject of FARs (field alert reports); and, (4) have any other kind of outcome that may indicate changes are needed. Where any of these categories include multiple problems, the number of batches selected for review should fully represent the different kinds of problems in each category. Every drug product must have at least one batch included in the annual review. Different products may not be grouped by "similar processes" or any other similar approach, because the necessary differences in the process and/or specifications which make each product unique may result in different manufacturing outcomes. Contact for further info: Nicholas Buhay, HFD-325, 301-594-0098; e-mail: buhay@cder.fda.gov Reprinted from: FDA's
HUMAN
DRUG CGMP NOTES (Volume 6, Number 1) March, 1998. Does FDA have any guidance regarding the color of ink used to prepare CGMP production records?Reference: No. However, whatever ink is used should permit the records to meet the inspection, review and archiving requirements in section 211.180 of the CGMP regulations. For example, for a record to be maintained for one year past the expiration date of the related lot, per 211.180(b), one needs to be able to read the record throughout the retention period. Likewise, per 211.180(c), the records are subject to FDA photocopying or other means of reproduction. In addition, paragraph (e) of this section requires that production records be maintained such that firms may review them at least annually to determine if production and control changes need to be made. Keeping these needs in mind, the ink that fades, can't be copied or otherwise obscures information would be troublesome. Contact for further information: Richard S. Lev, HFD-325, 301-594-0089, e-mail: levr@cder.fda.gov Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 5, Number 3) September, 1997. Do the CGMP requirements for records retention apply to the raw data generated in support of new drug applications?Reference: Yes, if the raw data are associated with drug products which are used in tests involving human subjects, or if the drug products are distributed to the market after NDA approval. Additionally, it is very important to realize that we consider the raw data generated in development of the application to be part of the application and therefore the data should be retained as long as the application is in effect. The new drug regulations require "an application to contain reports of all investigations of the drug product sponsored by the applicant, and all other information about the drug pertinent to an evaluation of an application that is received or other wise obtained by the applicant from any source." Contact for further information: Nicholas Buhay, HFD-325, 301-594-0098; e-mail: buhay@cder.fda.gov Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997. Are firms required to keep analytical stability data generated by a remote lab available for FDA inspection at the manufacturer's site?Reference: No. The CGMP regulations require that firms retain and make available during an FDA inspection all analytical data generated in the course of QC and stability testing. However, firms are not required to keep the data at the manufacturing site if the testing is performed at another location. Consequently, there are times when it is necessary to inspect an outside testing facility to audit pertinent analytical data as well as the testing facility's CGMP controls. If the testing is being conducted by a contract lab, the manufacturer is responsible for assuring the adequacy of the lab as well as for evaluating and performing appropriate follow-up to the test results. Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997. Must annual evaluations include failed batches? What if such batches are made for "research" purposes?Reference: Yes. 21 CFR 211.180(e) requires an annual evaluation of the quality standards of each drug product to determine the need for changes in specifications and/or manufacturing or control procedures. Failed batches made for commercial distribution must be included in the inventory of batches from which a number of batches are selected for a 211.180(e) annual review of the product. There is no category of manufacture which includes a batch which is intended for commercial distribution if it passes specifications upon testing and at the same time for "research", or "experimental", or any other similarly designated purpose, if it does not pass all specifications upon testing. The status of a batch is to be designated unequivocally and in advance. Equivocation in the status of a batch or changes in status from commercial distribution to research, etc. is unacceptable as good manufacturing practice, and may have data reliability implications. Obviously, information derived from the failed manufacture of a commercial batch may be used for research or product development purposes, but this does not change the commercial nature of the batch. Information on a failure of a batch of new drug product to meet a specification is required to be submitted to the A/NDA Annual Report under 21 CFR 314.81(b)(2)(i) and 314.81(b)(2)(iv) because it is "significant new information from the previous year that might effect the safety, efficacy, or labeling" and "new information that may affect FDA's previous conclusions about the safety or effectiveness of the drug product." FDA will accept as adequate to meet this requirement submission of a Section 314.81(b)(1) Field Alert Report on the incident, or inclusion in the A/NDA Annual Report. Contact for further info: Nicholas Buhay, HFD-325, 301594-0098, e-mail: buhay@cder.fda.gov . Reprinted from FDA's Human
Drug CGMP Notes, (Volume 4 Number 2), June, 1996. How long must a contract manufacturer, who performs only part of the production steps, retain records for those activities?References: See 21 CFR 211.180(a) and (b) (General requirements) The records retention requirements for the contractor are the same as those for the prime manufacturer, just as if the activities had been performed by the prime manufacturer. The retention time is at least one year after the expiration date of the drug product, or, in the case of some OTC drug products which are not required to have expiration dates, three years after the last of the batch has been distributed. The retention requirement for the contractor, therefore, means that the contractor must know what the dosage form expiration date is, or (for the above OTC products) when the last of the batch has been distributed. Where the contractor's activities are performed at some stage prior to formation of the dosage form itself (say a contract micronizer), some close communication with the dosage form producer would be needed. It is important for the contractor's records to be available so that complete product history is maintained and, more importantly, investigations of possible problems may be conducted. The records must be kept at the contract manufacturer's facility, per 211.180(c), or else the records (or copies of them) may be kept at a different location if they can be immediately retrieved by computer or other electronic means. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 3, Number 3) September, 1995. Part 11 Enforcement CPG PublishesCompliance Policy Guide (CPG) 7153.17 (Section 160.850); (1) Legacy systems (those in place before August 20, 1997, part 11's effective date). Older electronic records systems may not have reached full compliance by 8/20/97 and their modification may take more time. However, legacy systems are not grandfathered and FDA expects firms that use legacy systems will begin taking steps to achieve full compliance. (2) Regulatory action determinations. For all systems (legacy, too) decisions on whether or not non-compliance merits pursuit of regulatory action will be based on a case by case evaluation. The evaluation may include consideration of the:
(3) Headquarters consultation. Program monitors and center compliance offices should be consulted before recommending regulatory actions. (4) Regulatory citations. Regulatory citations should reference the applicable predicate regulations in addition to part 11. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 3) September, 1999. Under part 11, when a firm uses a contracted T1 line to a remote facility, is the system considered closed? Contrast this with communicating over the public Internet as being an open system.Reference: In classifying a system as open or closed, a firm needs to determine if it controls access to the system that holds records for which it is responsible. Lacking such control, its records could be vulnerable to unauthorized disclosure or modification; trade secret and confidential information may be at risk. Therefore, firms may wish to put into place added record protections such as encryption. Part 11 does not mandate those added controls in all cases, but rather permits firms to make that decision for themselves based on the circumstances. How well a firm safeguards its records may reflect the degree to which it regards the information as trade secret. Let's assume that the firm is responsible for the content of the records in question and that the remote facility holds the firm's records. First, we need to consider if the communications line to the facility uses store and forward technology, meaning the records are stored on one or more servers before arriving at the remote facility. If the firm controls who can access those intermediate holding systems as well as the remote facility itself, the records would be in a closed system from the firm's perspective. On the other hand, if the firm does not control access to either those intermediate holding systems or the final remote facility, the system would be open. Faced with an open system, the firm would need to evaluate the circumstances (such as the contents of the records themselves) and decide if added controls were warranted. On the Internet, store and forward technology is customary, and the firm would not control access to servers that held its records (i.e., the system would be open.) Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 2) June, 1999. With respect to 21 CFR 11.50, can the display of a user identification code (such as "Big Apple") be used to satisfy the requirement that the signer's printed name be displayed?Reference: No. A code used in this case is not the same as the signer's printed name. The printed name does not, however, have to be hard coded in the recordkeeping software in order to generate the display of the printed name. For example, a system could maintain a "look-up" table to identify and link the user name to a corresponding user identification code and password. Of course, if the system uses the individual's full name as the user identification in the first place, then it would meet the 11.50 requirement because the printed name and user id would be one and the same. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. Does FDA have a complete list of all possible electronic signature meanings? Must the meaning of an electronic signature be displayed each time in every place it appears? Can the meaning be assumed to be present by reference to a separate user manual or SOP?Reference: Part 11 requires that the meaning of a signature be displayed in human readable forms of a signed electronic record. FDA does not have a list of all possible signature meanings. Meanings of signatures are contextually determined and they are programmed in when the recordkeeping system is developed. When a signed electronic record is displayed in human readable form, what each signature means must be displayed either explicitly or contextually. In the drug CGMP arena, there are relatively few meanings to a signature (e.g., review, authorship, approval, and performance of an action such as a production step, sample collection or analysis.) It is possible that a record contains a single statement of meaning that applies to multiple signatures in the record. A cross reference to a manual or SOP would not meet this requirement if the signature meaning itself is not displayed in the record. The cross reference could be problematic, if, after a record is signed, the SOP is changed to indicate a new meaning that did not, in fact, apply at the time the record was signed. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 4) December, 1998. Can a firm that creates batch production records in electronic form archive them as paper only?Reference: No. Part 11 requires that electronic records be archived in electronic form. The electronic records must be protected to enable their accurate and ready retrieval throughout the relevant retention period set by the rule that applies to those records. In this case, 21 CFR 211.180 requires batch records to be kept for at least one year past the batch expiration date, or, for certain OTC products, three years after batch distribution. Part 11 also requires that firms be able to generate accurate and complete copies of electronic records in electronic as well as human readable form suitable for agency review, inspection, and copying. It is important to note that paper printouts are seldom accurate and complete copies of electronic records (paper records lack meta-data information such as time and date stamps, audit trails, and other information not intended to be printed.) Moreover, a major principle in part 11 is that for FDA to be able to protect and promote public health it must function on the same technological plane as the regulated industry. We couldn't do that if firms were allowed to destroy their electronic records and present to FDA investigators only paper archives because investigators would not be able to apply information technology based tools such as search and sort techniques when reviewing those records. Finally, considering that industry urged FDA to develop part 11 in large measure to reduce the burdens of paper recordkeeping, it is unlikely that firms would want to fall back to paper for archiving purposes. Contact for further info: Richard Lev, HFD-325, 301-594-0098; e-mail: levr@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 3) September, 1998. Does an electronic signature time stamp need to be local to the signer or to a central network when an electronic batch record system spans different time zones?Reference: The agency answered this question in the preamble to the final rule by saying "Regarding systems that may span different time zones, the agency advises that the signer's local time is the one to be recorded." Recording the local time is important to not only clearly document the sequence of events in human terms, but also help authenticate an electronic signature and minimize chances of signer repudiation. For example, the local time stamp can be correlated with the whereabouts of the purported signer to help establish authenticity; if the person who supposedly signed the record was at a meeting, or otherwise unable to sign the record at the time of signature execution, the time stamp would help show that an imposter executed the signature. A firm could then initiate an appropriate investigation. Part 11 does not, however, prohibit a firm from supplementing the local time stamp with the time stamp of a remote central server that may be in a different time zone from the signer. Where dual stamps are recorded, though, it is important that the electronic record clearly indicate which one is local to the signer. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
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